U.S. patent number 7,652,143 [Application Number 11/763,618] was granted by the patent office on 2010-01-26 for cyclic ureas used as inhibitors of metalloproteases.
This patent grant is currently assigned to sanofi-aventis Deutschland GmbH. Invention is credited to Jochen Beninga, Sven Grueneberg, Andreas Lindenschmidt, Holger Wagner, Klaus-ulrich Weithmann.
United States Patent |
7,652,143 |
Lindenschmidt , et
al. |
January 26, 2010 |
Cyclic ureas used as inhibitors of metalloproteases
Abstract
The present invention relates to a novel compound of the formula
I: ##STR00001## and/or all stereoisomeric forms of the compound of
the formula I and/or mixtures of these forms in any ratio, and/or a
physiologically tolerated salt of the compound of the formula I, in
which R1 to R5 and V1, V2 have the meanings stated in the claims
and specification. The inventive compounds are suitable as
inhibitors of metalloproteases, especially of ADAMTS proteases and
TNF-.alpha. converting enzyme (TACE), and for the treatment of
disorders such as but not limited to osteoarthrosis and rheumatoid
arthritis.
Inventors: |
Lindenschmidt; Andreas (Bad
Soden, DE), Wagner; Holger (Biberach/Mettenberg,
DE), Beninga; Jochen (Mainz, DE),
Grueneberg; Sven (Kelkheim, DE), Weithmann;
Klaus-ulrich (Hofheim, DE) |
Assignee: |
sanofi-aventis Deutschland GmbH
(Frankfurt am Main, DE)
|
Family
ID: |
35825373 |
Appl.
No.: |
11/763,618 |
Filed: |
June 15, 2007 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20080096918 A1 |
Apr 24, 2008 |
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Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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PCT/EP2005/012799 |
Dec 1, 2005 |
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Foreign Application Priority Data
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Dec 15, 2004 [DE] |
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10 2004 060 229 |
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Current U.S.
Class: |
546/272.7;
548/323.5; 548/318.5; 548/317.1; 548/134; 546/152 |
Current CPC
Class: |
A61P
1/14 (20180101); C07D 405/06 (20130101); A61P
9/10 (20180101); A61P 37/00 (20180101); A61P
9/04 (20180101); A61P 17/02 (20180101); A61P
35/00 (20180101); C07D 401/12 (20130101); A61P
35/04 (20180101); A61P 19/00 (20180101); A61P
19/08 (20180101); A61P 21/00 (20180101); C07D
233/34 (20130101); C07D 285/10 (20130101); A61P
1/04 (20180101); A61P 29/00 (20180101); C07D
233/36 (20130101); A61P 31/04 (20180101); A61P
19/02 (20180101); A61P 1/02 (20180101); A61P
43/00 (20180101) |
Current International
Class: |
C07D
401/00 (20060101); A61K 31/17 (20060101); C07D
233/00 (20060101) |
Field of
Search: |
;514/237.5,311,341,362,386,389,824,825,826 ;546/152,272.7
;548/317.1,318.5,323.5 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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2003MU00236 |
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Feb 2003 |
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IN |
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WO 98/32748 |
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Jul 1998 |
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WO |
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WO 2005077937 |
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Aug 2005 |
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WO |
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Primary Examiner: Marschel; Ardin
Assistant Examiner: Rao; Savitha
Attorney, Agent or Firm: Bolcsak; James W.
Claims
What is claimed is:
1. A compound of the formula I: ##STR00016## and/or all
stereoisomeric forms of the compound of the formula I and/or
mixtures of these forms in any ratio, and/or a physiologically
tolerated salt of the compound of the formula I, wherein, Z is
--C(O)--, R1 and R2 are identical or different and are
independently of one another hydrogen atom or
--(C.sub.1-C.sub.4)-alkyl, or R1 and R2 form together with the
carbon atom to which they are respectively bonded
--(C.sub.3-C.sub.6)-cycloalkyl, R3 and R4 are identical or
different and are independently of one another: a covalent bond,
--(CH.sub.2).sub.m-- or
--(C.sub.1-C.sub.3)-alkylene-O--(C.sub.0-C.sub.3)-alkylene-, in
which m is the integer 1, and in which the alkylene radical which
is formed by --(CH.sub.2).sub.m-- is unsubstituted or substituted
once by --OH, V.sub.2 is hydrogen atom, V.sub.1 and R5 are
identical or different and are independently of one another
hydrogen atom, --(C6-C14)-aryl in which aryl is phenyl and is
unsubstituted or substituted once or twice by R8 or the radical
-G-M, or a mono- or bicyclic 4- to 15-membered heterocycle in which
heterocycle is a radical from the series benzodioxol, quinolinyl or
pyridyl, in which the heterocycle is unsubstituted or substituted
once, twice or three times by R8 or the radical -G-M, M is:
hydrogen atom, --(C6-C14)-aryl in which aryl is phenyl and is
unsubstituted or substituted once or twice by R8, or a mono- or
bicyclic 4- to 15-membered heterocycle in which heterocycle is as
defined above and in which the heterocycle is unsubstituted or
substituted once, twice or three times by R8, R8 is halogen, --OH
or --(C1-C4)-alkyl or --O--(C1-C4)-alkyl, G is: covalent bond,
--(C0-C3)-alkylene-O--(C0-C3)-alkylene- or --(C0-C3)
-alkylene-O--(C2-C4)-alkenylene-, and Q is: covalent bond or
--(C1-C3)-alkylene, on condition that at least one of the radicals
V1 or R5 is --(C6-C14)-aryl or a mono- or bicyclic 4- to
15-membered heterocycle, in which aryl or heterocycle are
unsubstituted or substituted once or twice by R8 or the radical
-G-M; wherein the compound is selected from the following
compounds:
2-[3-(4-benzyloxybenzyl)-2-oxoimidazolidin-1-yl]-N-hydroxy-3-methylbutyra-
mide,
2-[3-(4-benzyloxyphenyl)-2-oxoimidazolidin-1-yl]-N-hydroxy-3-methylb-
utyramide,
2-[3-(3-benzyloxybenzyl)-2-oxoimidazolidin-1-yl]-N-hydroxy-3-me-
thylbutyramide,
N-hydroxy-3-methyl-2-[2-oxo-3-(4-phenoxybenzyl)imidazolidin-1-yl]-butyram-
ide,
2-[3-(6-benzyloxypyridin-3-ylmethyl)-2-oxoimidazolidin-1-yl]-N-hydrox-
y-3-methylbutyramide,
2-(3-biphenyl-4-ylmethyl-2-oxoimidazolidin-1-yl)-N-hydroxy-3-methylbutyra-
mide,
2-[3-benzyl-5-(4-methoxyphenyl)-2-oxoimidazolidin-1-yl]-N-hydroxy-3--
methylbutyramide,
N-hydroxy-2-[3-(4-hydroxybenzyl)-2-oxoimidazolidin-1-yl]-3-methylbutyrami-
de,
N-hydroxy-2-[3-(3-hydroxybenzyl)-2-oxoimidazolidin-1-yl]-3-methylbutyr-
amide,
N-hydroxy-3-methyl-2-{2-oxo-3-[4-(pyridin-4-ylmethoxy)benzyl]imidaz-
olidin-1-yl}butyramide with trifluoroacetic acid (TFA),
N-hydroxy-3-methyl-2-{2-oxo-3-[4-(pyridin-3-ylmethoxy)benzyl]imidazolidin-
-1-yl}butyramide with TFA,
N-hydroxy-3-methyl-2-{2-oxo-3-[4-(pyridin-2-ylmethoxy)benzyl]imidazolidin-
-1-yl}butyramide with TFA,
2-[3-(4-but-2-ynyloxybenzyl)-2-oxoimidazolidin-1-yl]-N-hydroxy-3-methylbu-
tyramide,
N-hydroxy-3-methyl-2-{3-[4-(2-methylquinolin-4-ylmethoxy)benzyl]-
-2-oxoimidazolidin-1-yl}butyramide with TFA,
2-[3-benzyl-5-(4-methoxybenzyl)-2-oxoimidazolidin-1-yl]-N-hydroxy-3-methy-
lbutyramide,
2-[3-(4-benzyloxybenzyl)-5-(4-methoxybenzyl)-2-oxoimidazolidin-1-yl]-N-hy-
droxy-3-methylbutyramide,
N-hydroxy-2-[5-(4-methoxybenzyl)-3-methyl-2-oxoimidazolidin-1-yl]-3-methy-
lbutyramide,
2-[5-benzo[1,3]dioxol-5-ylmethyl-3-(4-benzyloxybenzyl)-2-oxoimidazolidin--
1-yl]-N-hydroxy-3-methylbutyramide,
2-(5-benzo[1,3]dioxol-5-ylmethyl-3-benzyl-2-oxoimidazolidin-1-yl)-N-hydro-
xy-3-methylbutyramide or
2-[3-(4-benzyloxyphenyl)-2-oxo-[1,3]diazepan-1-yl]-N-hydroxy-3-methyl-but-
yramide.
2. A medicament having an effective amount of at least one compound
of the formula I as claimed in claim 1 together with a
pharmaceutically suitable and physiologically tolerated carrier,
additive and/or other active substances and excipients.
Description
FIELD OF THE INVENTION
The present invention relates to cyclic ureas which are suitable
for use as inhibitors of metalloproteases, especially of ADAMTS
proteases and TNF-.alpha. converting enzyme (TACE), to methods for
the preparation thereof and to the use thereof for the treatment of
disorders such as osteoarthrosis and rheumatoid arthritis.
BACKGROUND OF THE INVENTION
In the pathological state of osteoarthrosis, degradation of the
aggrecan, the main proteoglycan of articular cartilage, represents
a very early and crucial event. The pathological loss of the
cartilage aggrecan results from proteolytic cleavages in its
interglobular domain. Amino acid sequence analyses of proteoglycan
metabolites isolated from the synovial fluid of patients suffering
from joint damage, osteoarthrosis or an inflammatory joint disorder
have shown that a proteolytic cleavage takes place preferentially
between the amino acids Glu.sup.373 and Ala.sup.374 in the
interglobular domain of human aggrecan (Lohmander et al., Arthritis
Rheum. 36, (1993), 1214-1222). The proteolytic activity responsible
for this cleavage is referred to as "aggrecanase" and may be
assigned to the superfamily of metalloproteinases (MP).
Zinc is essential in the catalytically active site of
metalloproteinases. MPs cleave collagen, laminin, proteoglycans,
elastin or gelatin under physiological conditions and therefore
play an important role in bone and connective tissue. A large
number of different MP inhibitors are known (J. S. Skotnicki et
al., Ann. N.Y. Acad. Sci. 878, 61-72 (1999); EP 0 606 046;
WO94/28889). Some of these inhibitors are not well characterized in
relation to their specificity; others are more or less selectively
directed in particular against matrix metalloproteinases
(MMPs).
Aggrecanase differs from matrix metalloproteinases (MMPs) by its
different specificity, which is directed against particular
cleavage sites which occur in aggrecan and are not favored by MMPs.
The cleavage results in characteristic fragments which can be
detected by using suitable antibodies.
A frequent disadvantage of known inhibitors of MMPs is the lack of
specificity of the inhibition for only one class of MMPs. Most MMP
inhibitors therefore inhibit a plurality of MMPs
simultaneously.
In the endeavor to find effective compounds for the treatment of
connective issue disorders, it has now been found that the
compounds of the formula I are strong inhibitors of matrix
metalloproteinases such as aggrecanase, for example ADAMTS-4,
ADATMS-5 or ADAMTS-1 and tissue necoris factor .alpha.
(TNF-.alpha.) converting enzyme.
DETAILED DESCRIPTION OF THE INVENTION
The invention therefore relates to a compound of the formula I
##STR00002## and/or all stereoisomeric forms of the compound of the
formula I and/or mixtures of these forms in any ratio, and/or a
physiologically tolerated salt of the compound of the formula I,
where Z is --C(O)-- or --S(O).sub.2--, R1 and R2 are identical or
different and are independently of one another a) hydrogen atom, b)
--(C.sub.1-C.sub.6)-alkyl, c) --(C.sub.3-C.sub.6)-cycloalkyl, d)
--(C.sub.2-C.sub.4)-alkyl-Het, in which Het is a mono- or bicyclic
4- to 15-membered heterocycle which comprises at least one carbon
atom and one, two, three or four heteroatoms from the series
nitrogen, sulfur or oxygen, in which the heterocycle is
unsubstituted or substituted once, twice or three times by R8, or
e) --(C.sub.2-C.sub.4)-alkyl-(C.sub.6-C.sub.14)-aryl in which aryl
is unsubstituted or substituted once or twice by R8, or R1 and R2
form together with the carbon atom to which they are respectively
bonded a) --(C.sub.3-C.sub.6)-cycloalkyl or b) a mono- or bicyclic
4- to 15-membered heterocycle which comprises at least one carbon
atom and one, two, three or four heteroatoms from the series
nitrogen, sulfur or oxygen, in which the heterocycle is
unsubstituted or substituted once, twice or three times by R8, R3
and R4 are identical or different and are independently of one
another a covalent bond, --(CH.sub.2).sub.m--,
--(C.sub.1-C.sub.3)-alkylene-O--(C.sub.0-C.sub.3)-alkylene,
--(C.sub.0-C.sub.3)-alkylene-C(O)--O--(CH.sub.2).sub.n--,
--(C.sub.0-C.sub.3)-alkylene-C(O)--NR.sup.10--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.m--CH(OH)--(CH.sub.2).sub.n--,
--(C.sub.1-C.sub.3)-alkylene-N(R.sup.10)--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.m--NR.sup.10--C(O)--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.m--NR.sup.10--C(O)--NR.sup.10--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.m--O--C(O)--NR.sup.10--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.m--NR.sup.10--C(O)--O--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.m--S--(CH.sub.2).sub.n--,
--(C.sub.1-C.sub.3)-alkylene-S(O)--(CH.sub.2).sub.n--,
--(C.sub.1-C.sub.3)-alkylene-SO.sub.2--(CH.sub.2).sub.n--,
--(C.sub.1-C.sub.3)-alkylene-SO.sub.2--NH--(R.sup.10),
--(CH.sub.2).sub.m--SO.sub.2--NR.sup.10--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.m--NR.sup.10--SO.sub.2--(CH.sub.2).sub.n-- or
--(CH.sub.2).sub.m--NR.sup.10--SO.sub.2--NR.sup.10--(CH.sub.2).sub.n--,
in which n and m are independently of one another identical or
different, and m is the integers 1, 2, 3, 4, 5 or 6, and n is the
integers zero 1, 2, 3, 4, 5 or 6, and in which the alkylene
radicals which are formed by --(CH.sub.2).sub.m-- or
--(CH.sub.2).sub.n-- are unsubstituted or substituted once, twice
or three times by halogen, --NH.sub.2 or --OH or form a
--(C.sub.3-C.sub.6)-cycloalkyl in which cycloalkyl is unsubstituted
or substituted once, twice or three times by halogen, --NH.sub.2 or
--OH, R.sup.10 is hydrogen atom, --(C.sub.1-C.sub.6)-alkyl,
--(C.sub.0-C.sub.4)-alkyl-OH,
--(C.sub.0-C.sub.4)-alkyl-O--(C.sub.1-C.sub.4)-alkyl or
--(C.sub.1-C.sub.3)-perfluoroalkyl, V.sub.1, V.sub.2 and R5 are
identical or different and are independently of one another a)
hydrogen atom, b) --(C.sub.6-C.sub.14)-aryl in which aryl is
unsubstituted or substituted once or twice by R8 or the radical
-G-M, or c) a mono- or bicyclic 4- to 15-membered heterocycle which
comprises at least one carbon atom and one, two, three or four
heteroatoms from the series nitrogen, sulfur or oxygen, in which
the heterocycle is unsubstituted or substituted once, twice or
three times by R8 or the radical -G-M, M is a) hydrogen atom, b)
--(C.sub.6-C.sub.14)-aryl in which aryl is unsubstituted or
substituted once or twice by R8, or c) a mono- or bicyclic 4- to
15-membered heterocycle which comprises at least one carbon atom
and one, two, three or four heteroatoms from the series nitrogen,
sulfur or oxygen, and in which the heterocycle is unsubstituted or
substituted once, twice or three times by R8, R8 is 1) halogen, 2)
--NO.sub.2, 3) --CN, 4) --C(O)--NH.sub.2, 5) --SO.sub.2--NH.sub.2,
6) --OH, 7) --NH.sub.2, 8) --O--CF.sub.3, 9)
--(C.sub.6-C.sub.14)-aryl in which aryl is unsubstituted or
substituted once or twice by halogen or
--O--(C.sub.1-C.sub.8)-alkyl, 10) --(C.sub.1-C.sub.8)-alkyl in
which alkyl is unsubstituted or substituted once, twice or three
times by halogen, NH.sub.2, --OH or methoxy, 11)
--O--(C.sub.1-C.sub.8)-alkyl in which alkyl is unsubstituted or
substituted once, twice or three times by halogen, NH.sub.2, --OH
or methoxy, 12) --SO.sub.2--CH.sub.3 or 13) --SO.sub.2--CF.sub.3, G
is covalent bond, --(CH.sub.2).sub.o--,
--(C.sub.0-C.sub.3)-alkylene-O--(C.sub.0-C.sub.3)-alkylene-,
--(C.sub.0-C.sub.3)-alkylene-C(O)--O--(CH.sub.2).sub.p--,
--(C.sub.0-C.sub.3)-alkylene-C(O)--NR.sup.10--(CH.sub.2).sub.p--,
--(CH.sub.2).sub.o--CH(OH)--(CH.sub.2).sub.p--,
--(C.sub.0-C.sub.3)-alkylene-N(R.sup.10)--(CH.sub.2).sub.p--,
--(CH.sub.2).sub.o--NR.sup.10--C(O)--(CH.sub.2).sub.p--,
--(CH.sub.2).sub.o--NR.sup.10--C(O)--NR.sup.10--(CH.sub.2).sub.p--,
--(CH.sub.2).sub.0--O--C(O)--NR.sup.10--(CH.sub.2).sub.p--,
--(CH.sub.2).sub.o--NR.sup.10--C(O)--O--(CH.sub.2).sub.p--,
--(CH.sub.2).sub.o--S--(CH.sub.2).sub.p--,
--(C.sub.0-C.sub.3)-alkylene-S(O)--(CH.sub.2).sub.p--,
--(C.sub.0-C.sub.3)-alkylene-SO.sub.2--(CH.sub.2).sub.p--,
--(C.sub.0-C.sub.3)-alkylene-SO.sub.2--NH--(R.sup.10),
--(CH.sub.2).sub.o--SO.sub.2--NR.sup.10--(CH.sub.2).sub.p--,
--(CH.sub.2).sub.o--NR.sup.10--SO.sub.2--(CH.sub.2).sub.p--,
--(C.sub.0-C.sub.3)-alkylene-O--(C.sub.2-C.sub.4)-alkenylene- or
--(CH.sub.2).sub.o--NR.sup.10--SO.sub.2--NR.sup.10--(CH.sub.2).sub.p--,
in which o and p are identical or different and are independently
of one another the integers zero, 1, 2, 3, 4, 5 or 6, and in which
the alkylene radicals which are formed by --(CH.sub.2).sub.o-- or
--(CH.sub.2).sub.p-- are unsubstituted or substituted once, twice
or three times by halogen, --NH.sub.2 or --OH or form a
--(C.sub.3-C.sub.6)-cycloalkyl in which cycloalkyl is unsubstituted
or substituted once, twice or three times by halogen, --NH.sub.2 or
--OH, and R10 is as defined above, and Q is covalent bond,
--(C.sub.1-C.sub.3)-alkylene or --(C.sub.3-C.sub.6)-cycloalkyl, on
condition that at least one of the radicals V.sub.1, V.sub.2 or R5
is --(C.sub.6-C.sub.14)-aryl or a mono- or bicyclic 4- to
15-membered heterocycle, in which aryl or heterocycle are
unsubstituted or substituted once or twice by R8 or the radical
-G-M. 2) The invention further relates to the compound of the
formula I where Z is --C(O)-- or --S(O).sub.2--, R1 and R2 are
identical or different and are independently of one another
hydrogen atom or --(C.sub.1-C.sub.4)-alkyl, or R1 and R2 form
together with the carbon atom to which they are respectively bonded
--(C.sub.3-C.sub.6)-cycloalkyl, R3 and R4 are identical or
different and are independently of one another a covalent bond,
--(CH.sub.2).sub.m--,
--(C.sub.1-C.sub.3)-alkylene-O--(C.sub.0-C.sub.3)-alkylene-,
--(C.sub.0-C.sub.3)-alkylene-C(O)--O--(CH.sub.2).sub.n--,
--(C.sub.0-C.sub.2)-alkylene-C(O)--NR.sup.10--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.m--CH(OH)--(CH.sub.2).sub.n--,
--(C.sub.1-C.sub.3)-alkylene-N(R.sup.10)--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.m--NR.sup.10--C(O)--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.m--NR.sup.10--C(O)--NR.sup.10--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.m--O--C(O)--NR.sup.0--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.m--NR.sup.10--C(O)--O--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.m--S--(CH.sub.2).sub.n--,
--(C.sub.1-C.sub.3)-alkylene-S(O)--(CH.sub.2).sub.n--,
--(C.sub.1-C.sub.3)-alkylene-SO.sub.2--(CH.sub.2).sub.n--,
--(C.sub.1-C.sub.3)-alkylene-SO.sub.2--NH--(R.sup.10),
--(CH.sub.2).sub.m--SO.sub.2--NR.sup.10--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.m--NR.sup.10--SO.sub.2--(CH.sub.2).sub.n-- or
--(CH.sub.2).sub.m--NR.sup.10--SO.sub.2--NR.sup.10--(CH.sub.2).sub.n--,
in which n and m are independently of one another identical or
different, and m is the integers 1, 2, 3, 4, 5 or 6, and n is the
integers zero, 1, 2, 3, 4, 5 or 6, and in which the alkylene
radicals which are formed by --(CH.sub.2).sub.m-- or
--(CH.sub.2).sub.n-- are unsubstituted or substituted once, twice
or three times by halogen, --NH.sub.2 or --OH or form a
--(C.sub.3-C.sub.6)-cycloalkyl in which cycloalkyl is unsubstituted
or substituted once, twice or three times by halogen, --NH.sub.2 or
--OH, R.sup.10 is hydrogen atom, --(C.sub.1-C.sub.6)-alkyl,
--(C.sub.0-C.sub.4)-alkyl-OH,
--(C.sub.0-C.sub.4)-alkyl-O--(C.sub.1-C.sub.4)-alkyl or
--(C.sub.1-C.sub.3)-perfluoroalkyl, V.sub.1, V.sub.2 and R5 are
identical or different and are independently of one another a)
hydrogen atom, b) --(C.sub.6-C.sub.14)-aryl in which aryl is a
radical from the series phenyl, naphthyl, 1-naphthyl, 2-naphthyl,
anthryl or fluorenyl, is unsubstituted or substituted once or twice
by R8 or the radical -G-M, or c) a mono- or bicyclic 4- to
15-membered heterocycle in which heterocycle is a radical from the
series acridinyl, azetidinyl, benzimidazolyl, benzodioxol,
benzodiazin, benzofuranyl, benzothiofuranyl, benzothiophenyl,
benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl,
benzisoxazolyl, benzisothiazolyl, benzimidazalinyl, carbazolyl,
beta-carbolinyl, quinazolinyl, quinolinyl, 4H-quinolizinyl,
quinoxalinyl, quinuclidinyl, chromanyl, chromenyl,
decahydroquinolinyl, dihydrofuran, dithiazinyl, dithiazolly,
fuaranyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl,
1H-indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl,
isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl,
isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl,
naphthyridinyl, octahydro-isoquinolinyl, oxadiazolyl,
1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,
1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl,
phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl,
phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl,
piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl,
pyro-azolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl,
pryidooxazolyl, pyridoimidazolyl, pyridothiazolyl,
pyridothiophenyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl,
pyrrolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl,
tetrahydroquinolinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,
1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,
thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl,
triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl,
1,3,4-triazolyl and xanthenyl, in which the heterocycle is
unsubstituted or substituted once, twice or three times by R8 or
the radical -G-M, M is a) hydrogen atom, b)
--(C.sub.6-C.sub.14)-aryl in which aryl is as defined above and is
unsubstituted or substituted once or twice by R8, or c) a mono- or
bicyclic 4- to 15-membered heterocycle in which heterocycle is as
defined above, and in which the heterocycle is unsubstituted or
substituted once, twice or three times by R8, R.sup.8 is 1)
halogen, 2) --NO.sub.2, 3) --CN, 4) --C(O)--NH.sub.2, 5)
--SO.sub.2--NH.sub.2, 6) --OH, 7) --NH.sub.2, 8) --O--CF.sub.3, 9)
--(C.sub.6-C.sub.14)-aryl in which aryl is unsubstituted or
substituted once or twice by halogen or
--O--(C.sub.1-C.sub.8)-alkyl, 10) --(C.sub.1-C.sub.8)-alkyl in
which alkyl is unsubstituted or substituted once, twice or three
times by halogen, NH.sub.2, --OH or methoxy, 11)
--O--(C.sub.1-C.sub.8)-alkyl in which alkyl is unsubstituted or
substituted once, twice or three times by halogen, NH.sub.2, --OH
or methoxy, 12) --SO.sub.2--CH.sub.3 or 13) --SO.sub.2--CF.sub.3, G
is covalent bond, --(CH.sub.2).sub.o--,
--(C.sub.0-C.sub.3)-alkylene-O--(C.sub.0-C.sub.3)-alkylene,
--(CH.sub.2).sub.o--CH(OH)--(CH.sub.2).sub.p--,
--(C.sub.0-C.sub.3)-alkylene-C(O)--O--(CH.sub.2).sub.p--,
--(C.sub.0-C.sub.3)-alkylene-C(O)--NR.sup.10--(CH.sub.2).sub.p--,
--(C.sub.0-C.sub.3)-alkylene-N(R.sup.10)--(CH.sub.2).sub.p--,
--(CH.sub.2).sub.o--NR.sup.10--C(O)--(CH.sub.2).sub.p--,
--(CH.sub.2).sub.0--O--C(O)--NR.sup.10--(CH.sub.2).sub.p--,
--(CH.sub.2).sub.o--NR.sup.10--C(O)--NR.sup.10--(CH.sub.2).sub.p--,
--(CH.sub.2).sub.o--NR.sup.10--C(O)--O--(CH.sub.2).sub.p--,
--(CH.sub.2).sub.o--S--(CH.sub.2).sub.p--,
--(C.sub.0-C.sub.3)-alkylene-S(O)--(CH.sub.2).sub.p--,
--(C.sub.0-C.sub.3)-alkylene-SO.sub.2--(CH.sub.2).sub.p--,
--(C.sub.0-C.sub.3)-alkylene-SO.sub.2--NH--(R.sup.10),
--(CH.sub.2).sub.o--SO.sub.2--NR.sup.10--(CH.sub.2).sub.p--,
--(CH.sub.2).sub.o--NR.sup.10--SO.sub.2--(CH.sub.2).sub.p--,
--(C.sub.0-C.sub.3)-alkylene-O--(C.sub.2-C.sub.4)-alkenylene-, or
--(CH.sub.2).sub.o--NR.sup.10--SO.sub.2--NR.sup.10--(CH.sub.2).sub.p--,
in which o and p are identical or different and are independently
of one another the integers zero, 1, 2, 3, 4, 5 or 6, and in which
the alkylene radicals which are formed by --(CH.sub.2).sub.o-- or
--(CH.sub.2).sub.p-- are unsubstituted or substituted once, twice
or three times by halogen, --NH.sub.2 or --OH or
--(C.sub.3-C.sub.6)-cycloalkyl in which cycloalkyl is unsubstituted
or substituted once, twice or three times by halogen, --NH.sub.2 or
--OH, and R10 is as defined above, and Q is covalent bond,
--(C.sub.1-C.sub.3)-alkylene or --(C.sub.3-C.sub.6)-cycloalkyl, on
condition that at least one of the radicals V.sub.1, V.sub.2 or R5
is --(C.sub.6-C.sub.14)-aryl or a mono- or bicyclic 4- to
15-membered heterocycle, in which aryl or heterocycle are
unsubstituted or substituted once or twice by R8 or the radical
-G-M. 3) The invention further relates to the compound of the
formula I where Z is --C(O)--, R1 and R2 are identical or different
and are independently of one another hydrogen atom or
--(C.sub.1-C.sub.4)-alkyl, or R1 and R2 form together with the
carbon atom to which they are respectively bonded
--(C.sub.3-C.sub.6)-cycloalkyl, R3 and R4 are identical or
different and are independently of one another a covalent bond,
--(CH.sub.2).sub.m-- or
--(C.sub.1-C.sub.3)-alkylene-O--(C.sub.0-C.sub.3)-alkylene-, in
which m is the integer 1, and in which the alkylene radical which
is formed by --(CH.sub.2).sub.m-- is unsubstituted or substituted
once by --OH, V.sub.2 is hydrogen atom, V.sub.1 and R5 are
identical or different and are independently of one another a)
hydrogen atom, b) --(C.sub.6-C.sub.14)-aryl in which aryl is phenyl
and is unsubstituted or substituted once or twice by R8 or the
radical -G-M, or c) a mono- or bicyclic 4- to 15-membered
heterocycle in which heterocycle is a radical from the series
benzodioxol, quinolinyl or pyridyl, in which the heterocycle is
unsubstituted or substituted once, twice or three times by R8 or
the radical -G-M, M is a) hydrogen atom, b)
--(C.sub.6-C.sub.14)-aryl in which aryl is phenyl and is
unsubstituted or substituted once or twice by R8, or c) a mono- or
bicyclic 4- to 15-membered heterocycle in which heterocycle is as
defined above and in which the heterocycle is unsubstituted or
substituted once, twice or three times by R8, R8 is halogen, --OH
or --(C.sub.1-C.sub.4)-alkyl or --O--(C.sub.1-C.sub.4)-alkyl, G is
covalent bond,
--(C.sub.0-C.sub.3)-alkylene-O--(C.sub.0-C.sub.3)-alkylene- or
--(C.sub.0-C.sub.3)-alkylene-O--(C.sub.2-C.sub.4)-alkenylene-, and
Q is covalent bond or --(C.sub.1-C.sub.3)-alkylene, on condition
that at least one of the radicals V.sub.1 or R5 is
--(C.sub.6-C.sub.14)-aryl or a mono- or bicyclic 4- to 15-membered
heterocycle, in which aryl or heterocycle are unsubstituted or
substituted once or twice by R8 or the radical -G-M. 4) The
invention further relates to compounds of the formula I from the
series
2-(3-(4-benzyloxybenzyl)-2-oxoimidazolidin-1-yl)-N-hydroxy-3-methy-
lbutyramide,
2-(3-(4-benzyloxyphenyl)-2-oxoimidazolidin-1-yl)-N-hydroxy-3-methylbutyra-
mide,
2-(3-(3-benzyloxybenzyl)-2-oxoimidazolidin-1-yl)-N-hydroxy-3-methylb-
utyramide,
N-hydroxy-3-methyl-2-(2-oxo-3-(4-phenoxybenzyl)imidazolidin-1-y-
l)butyramide,
2-(3-(6-benzyloxypyridin-3-ylmethyl)-2-oxoimidazolidin-1-yl)-N-hydroxy-3--
methylbutyramide,
2-(3-biphenyl-4-ylmethyl-2-oxoimidazolidin-1-yl)-N-hydroxy-3-methylbutyra-
mide,
2-(3-benzyl-5-(4-methoxyphenyl)-2-oxoimidazolidin-1-yl)-N-hydroxy-3--
methylbutyramide,
N-hydroxy-2-(3-(4-hydroxybenzyl)-2-oxoimidazolidin-1-yl)-3-methylbutyrami-
de,
N-hydroxy-2-(3-(3-hydroxybenzyl)-2-oxoimidazolidin-1-yl)-3-methylbutyr-
amide,
N-hydroxy-3-methyl-2-{2-oxo-3-(4-(pyridin-4-ylmethoxy)benzyl)imidaz-
olidin-1-yl}-butyramide with TFA,
N-hydroxy-3-methyl-2-{2-oxo-3-(4-(pyridin-3-ylmethoxy)benzyl)imidazolidin-
-1-yl}-butyramide with TFA,
N-hydroxy-3-methyl-2-{2-oxo-3-(4-(pyridin-2-ylmethoxy)benzyl)imidazolidin-
-1-yl}-butyramide with TFA,
2-(3-(4-but-2-ynyloxybenzyl)-2-oxoimidazolidin-1-yl)-N-hydroxy-3-methylbu-
tyramide,
N-hydroxy-3-methyl-2-{3-(4-(2-methylquinolin-4-ylmethoxy)benzyl)-
-2-oxoimidazolidin-1-yl}butyramide with TFA,
2-(3-benzyl-5-(4-methoxybenzyl)-2-oxoimidazolidin-1-yl)-N-hydroxy-3-methy-
lbutyramide,
2-(3-(4-benzyloxybenzyl)-5-(4-methoxybenzyl)-2-oxoimidazolidin-1-yl)-N-hy-
droxy-3-methylbutyramide,
N-hydroxy-2-(5-(4-methoxybenzyl)-3-methyl-2-oxoimidazolidin-1-yl)-3-methy-
lbutyramide,
2-(5-benzo(1,3)dioxol-5-ylmethyl-3-(4-benzyloxybenzyl)-2-oxoimidazolidin--
1-yl)-N-hydroxy-3-methylbutyramide,
2-(5-benzo(1,3)dioxol-5-ylmethyl-3-benzyl-2-oxoimidazolidin-1-yl)-N-hydro-
xy-3-methylbutyramide,
2-(5-(4-benzyloxybenzyl)-3-(4-methoxybenzyl)-1,1-dioxo-(1,2,5)thiadiazoli-
din-2-yl)-N-hydroxy-3-methylbutyramide or
2-(3-(4-benzyloxyphenyl)-2-oxo-(1,3)diazepan-1-yl)-N-hydroxy-3-methylbuty-
ramide.
The term "--(C.sub.1-C.sub.6)-alkyl" means hydrocarbon radicals
whose carbon chain is straight-chain or branched and comprises 1 to
6 carbon atoms, for example methyl, ethyl, propyl, isopropyl,
butyl, isobutyl, tertiary butyl, pentyl, isopentyl, neopentyl,
hexyl, 2,3-dimethylbutane or neohexyl.
The term "--(CH.sub.2).sub.o-- in which o is the number zero, 1, 2,
3, 4, 5 or 6" means when o is zero a covalent bond, o is 1 the
methylene radical, o is 2 the ethylene radical, o is 3 propylene, o
is 4 butenylene, o is 5 pentylene and o is 6 hexylene. The meanings
of the term "--(CH.sub.2).sub.p-- in which p is the number zero, 1,
2, 3, 4, 5 or 6" are analogous to the term
--(CH.sub.2).sub.o--.
The term "--(CH.sub.2).sub.n-- in which n is the integer zero, 1,
2, 3, 4, 5 or 6" means when n is zero a covalent bond, n is 1 the
methylene radical, n is 2 the ethylene radical, n is 3 propylene, n
is 4 butenylene, n is 5 pentylene and n is 6 hexylene. The meanings
of the term "--(CH.sub.2).sub.m-- in which m is the number 1, 2, 3,
4, 5 or 6" are analogous to the term --(CH.sub.2).sub.n--.
The term "--(C.sub.0-C.sub.3)-alkylene-" means hydrocarbon radicals
whose carbon chain is straight-chain or branched and comprises 1 to
3 carbon atoms, such as the radicals methylene, ethylene or
propylene. The term "--C.sub.0-alkylene-" means a covalent
bond.
The term "--(C.sub.2-C.sub.4)-alkenylene" means hydrocarbon
radicals whose carbon chain is straight-chain or branched and
comprises 2 to 4 carbon atoms and have, depending on the chain
length, 1 or 2 double bonds, for example ethenylene, propenylene,
isopropenylene, isobutenylene or butenylene; the substituents on
the double bond may, where the possibility exists in principle, be
arranged in the E or Z configuration.
The term "halogen" means fluorine, chlorine, bromine or iodine.
The term "--(C.sub.3-C.sub.6)-cycloalkyl" means radicals such as
compounds which are derived from 3- to 6-membered monocycles such
as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
The term "--(C.sub.1-C.sub.3)-perfluoroalkyl" means partly or
completely fluorinated alkyl radicals which are derived from the
following radicals such as --CF.sub.3, --CHF.sub.2, --CH.sub.2F,
--CHF--CF.sub.3, --CHF--CHF.sub.2, --CHF--CH.sub.2F,
--CH.sub.2--CF.sub.3, --CH.sub.2--CHF.sub.2, --CH.sub.2--CH.sub.2F,
--CF.sub.2--CF.sub.3, --CF.sub.2--CHF.sub.2, --CF.sub.2--CH.sub.2F,
--CH.sub.2--CHF--CF.sub.3, --CH.sub.2--CHF--CHF.sub.2,
--CH.sub.2--CHF--CH.sub.2F, --CH.sub.2--CH.sub.2--CF.sub.3,
--CH.sub.2--CH.sub.2--CHF.sub.2, --CH.sub.2--CH.sub.2--CH.sub.2F,
--CH.sub.2--CF.sub.2--CF.sub.3, --CH.sub.2--CF.sub.2--CHF.sub.2,
--CH.sub.2--CF.sub.2--CH.sub.2F, --CHF--CHF--CF.sub.3,
--CHF--CHF--CHF.sub.2, --CHF--CHF--CH.sub.2F,
--CHF--CH.sub.2--CF.sub.3, --CHF--CH.sub.2--CHF.sub.2,
--CHF--CH.sub.2--CH.sub.2F, --CHF--CF.sub.2--CF.sub.3,
--CHF--CF.sub.2--CHF.sub.2, --CHF--CF.sub.2--CH.sub.2F,
--CF.sub.2--CHF--CF.sub.3, --CF.sub.2--CHF--CHF.sub.2,
--CF.sub.2--CHF--CH.sub.2F, --CF.sub.2--CH.sub.2--CF.sub.3,
--CF.sub.2--CH.sub.2--CHF.sub.2, --CF.sub.2--CH.sub.2--CH.sub.2F,
--CF.sub.2--CF.sub.2--CF.sub.3, --CF.sub.2--CF.sub.2--CHF.sub.2 or
--CF.sub.2--CF.sub.2--CH.sub.2F.
The term "--(C.sub.6-C.sub.14)-aryl" means aromatic carbon radicals
having 6 to 14 carbon atoms in the ring. --(C.sub.6-C.sub.14)-Aryl
radicals are for example phenyl, naphthyl, for example 1-naphthyl,
2-naphthyl, biphenylyl, for example 2-biphenylyl, 3-biphenylyl and
4-biphenylyl, anthryl or fluorenyl. Biphenylyl radicals, naphthyl
radicals and, in particular, phenyl radicals are preferred aryl
radicals.
The term "a mono- or bicyclic 4- to 15-membered heterocycle which
comprises at least one carbon atom and one, two, three or four
heteroatoms from the series nitrogen, sulfur or oxygen" or "Het"
means radicals such as acridinyl, azetidinyl, benzimidazolyl,
benzodioxol, benzodiazine, benzofuranyl, benzothiofuranyl,
benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl,
benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalinyl,
carbazolyl, beta-carbolinyl, quinazolinyl, quinolinyl,
4H-quinolizinyl, quinoxalinyl, quinuclidinyl, chromanyl, chromenyl,
decahydroquinolinyl, dihydrofuran, dithiazinyl, dithiazolly,
fuaranyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl,
1H-indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl,
isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl,
isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl,
naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl,
1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,
1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl,
phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl,
phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl,
piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl,
pyro-azolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl,
pryidooxazolyl, pyridoimidazolyl, pyridothiazolyl,
pyridothiophenyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl,
pyrrolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl,
tetrahydroquinolinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,
1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,
thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl,
triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl,
1,3,4-triazolyl and xanthenyl.
Preferred heterocycle radicals are benzodioxol, benzofuranyl,
benzothiophenyl, 1,3-benzodioxolyl, benzimidazolyl, benzoxazolyl,
benzothiazolyl, quinolinyl, chromanyl, isochromanyl, quinazolinyl,
quinoxalinyl, furyl, imidazolyl, indazolyl, indolyl, isoquinolinyl,
isoindolyl, isothiazolyl, isoxazolyl, oxazolyl, phthalazinyl,
pteridinyl, purinyl, pyrazinyl, pyrazolyl, pyridazinyl,
pyridoimidazolyl, pyridopyridinyl, pyridopyrimidinyl, pyridyl,
pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl and thienyl.
Acidic or basic products of the compound of the formula I may be in
the form of their salts or in free form. Pharmacologically
acceptable salts are preferred, for example alkali metal or
alkaline earth metal salts, or hydrochlorides, hydrobromides,
sulfates, hemisulfates, all possible phosphates, and salts of amino
acids, natural bases or carboxylic acids.
Physiologically tolerated salts are prepared from compounds of the
formula I which are capable of salt formation, including their
stereoisomeric forms, by method step d) in a manner known per se.
The compounds of the formula I form stable alkali metal, alkaline
earth metal or optionally substituted ammonium salts with basic
reagents such as hydroxides, carbonates, bicarbonates, alcoholates,
and ammonia or organic bases, for example trimethyl- or
triethylamine, ethanolamine, diethanolamine or triethanolamine,
trometamol or else basic amino acids, for instance lysine,
ornithine or arginine. Where the compounds of the formula I have
basic groups, stable acid addition salts can also be prepared with
strong acids. Suitable for this purpose are both inorganic and
organic acids such as hydrochloric, hydrobromic, sulfuric,
hemisulfuric, phosphoric, methanesulfonic, benzenesulfonic,
p-toluenesulfonic, 4-bromobenzenesulfonic, cyclohexylamidosulfonic,
trifluoromethylsulfonic, 2-hydroxyethanesulfonic, acetic, oxalic,
tartaric, succinic, glycerolphosphoric, lactic, malic, adipic,
citric, fumaric, maleic, gluconic, glucuronic, palmitic, or
TFA.
The invention further relates to a method for preparing the
compound of the formula I and/or a stereoisomeric form of the
compound of the formula I and/or a physiologically tolerated salt
of the compound of the formula I, which comprises a) converting a
compound of the formula II
##STR00003## with a compound X-Q-R5 in which Q and R5 are defined
as in the compound of the formula I, and X is a halogen, into a
compound of the formula III
##STR00004## and converting with a compound of the formula IV
##STR00005## in which R1 and R2 are defined as in formula I, X is a
halogen, and R is a carboxyl protective group, into a compound of
the formula V
##STR00006## and subsequently converting the compound of the
formula V into the hydroxamic acid, in which Y is NH--OH, of the
formula I, or b) converting a compound of the formula VI
##STR00007## in which R1, R2, R3 and V1 are defined as in formula
I, and R is a carboxy protective group, with a compound
NH.sub.2-Q-R5 in which Q and R5 are defined as in the compound of
the formula I, into a compound of the formula VII
##STR00008## and subsequently converting with COCl.sub.2 or
SOCl.sub.2 into a compound of the formula VIII
##STR00009## and subsequently converting the compound of the
formula VIII into the hydroxamic acid, in which Y is NH--OH, of the
formula I, or c) fractionating a compound of the formula I which
has been prepared by method a) or b) and which, owing to its
chemical structure, occurs in enantiomeric forms into the pure
enantiomers by salt formation with enantiopure acids or bases,
chromatography on chiral stationary phases or derivatization using
chiral enantiopure compounds such as amino acids, separating the
diastereomers obtained thus, and eliminating the chiral auxiliary
groups, or d) either isolating in free form the compound of the
formula I which has been prepared by methods a), b), or c) or, in
the case where acidic or basic groups are present, converting into
physiologically tolerated salts.
Syntheses of compounds of the formula III are described in the
prior art, for example for Q=CH.sub.2 and R5=2-chloropyridyl in J.
Med. Chem. 1999, 42(12), 2227. Reaction with a halide of the
formula X-Q-R5 proceeds in the presence of a base such as potassium
carbonate, cesium carbonate, sodium hydride, lithium
diisopropylamide or lithium bis(trimethylsilyl)amide.
Compounds of the formula V can be prepared from compounds of the
formula III by deprotonation with a base such as lithium
bis(trimethylsilyl)amide, lithium diisopropylamide, potassium
carbonate, cesium carbonate or sodium hydride and alkylation with
compounds of the formula IV, for example described in Bioorg. Med.
Chem. Lett. 2002, 12(1), 25.
Compounds of the formula V are converted into the hydroxamic acid
of the formula I by deprotection of the carboxyl function in a
suitable way and conversion of the free carboxylic acid in analogy
to the known methods as described in WO97/18194 or Tetrahedron
Lett. 1992, 33(14), 1827. Suitable carboxyl protective groups for
compounds of the formula IV are for example esters such as t-butyl,
benzyl, isopropyl, ethyl or methyl esters. Cleavage thereof, and
further suitable protective groups for the carboxyl function, are
described in "Protective Groups in Organic Synthesis" T. W. Greene,
P. G. M. Wuts, John Wiley & Sons, Inc., 1999, pages
369-431.
Compounds of the formula VI can be converted into compounds of the
formula VII by reaction with amines of the type NH.sub.2-Q-R5 in
the presence of a base such as cesium carbonate, potassium
carbonate, triethylamine, diisopropylethylamine. Instead of an
addition base, this is also possible to employ the amine
NH.sub.2-Q-R5 in excess (greater than two mole equivalents) as
described in Tetrahedron Lett. 1999, 40(43), 7687.
Procedures for converting compounds of the formula VII into
compounds of the formula VIII are known. Thus, for example, this is
possible for Z=CO by reaction with phosgene, triphosgene or
carbonyldiimidazole, as described in J. Med. Chem. 1992, 35(5),
823. This is possible for Z=SO.sub.2 by reacting compounds of the
formula VII with SO.sub.2Cl.sub.2 as described in J. Org. Chem.
1987, 52(4), 479 or by reaction with SOCl.sub.2 in analogy to
Tetrahedron Lett. 1989, 30(29), 3873. Several methods known from
the literature are available for the subsequent oxidation, as
described in J. Med. Chem. 1981, 24(11), 1300 or Tetrahedron Lett.
2001, 42(8), 1433.
Compounds of the formula VIII can be converted in analogy to
compounds of the formula V into hydroxamic acids of the formula
I.
In process step c), the compound of the formula I is, if it occurs
as mixture of diastereomers or enantiomers or results as mixtures
thereof in the chosen synthesis, is separated into the pure
stereoisomers, either by chromatography on an optionally chiral
support material or, if the racemic compound of the formula I is
capable of salt formation, by fractional crystallization of the
diastereomeric salts formed with an optically active base or acid
as auxiliary. Examples of suitable chiral stationary phases for
thin-layer or column chromatographic separation of enantiomers are
modified silica gel supports (called Pirkle phases) and high
molecular weight carbohydrates such as triacetylcellulose. For
analytical purposes, gas chromatographic methods on chiral
stationary phases can also be used after appropriate derivatization
known to the skilled worker. To separate enantiomers of the racemic
carboxylic acids, diastereomeric salts differing in solubility are
formed using an optically active, usually commercially available,
base such as (-)-nicotine, (+)- and (-)-phenylethylamine, quinine
bases, L-lysine or L- and D-arginine, the less soluble component is
isolated as solid, the more soluble diastereomer is deposited from
the mother liquor, and the pure enantiomers are obtained from the
diastereomeric salts obtained in this way. It is possible in the
same way in principle to convert the racemic compounds of the
formula I containing a basic group such as an amino group with
optically active acids such as (+)-camphor-10-sulfonic acid, D- and
L-tartaric acid, D- and L-lactic acid and (+) and (-)-mandelic acid
into the pure enantiomers. Chiral compounds containing alcohol or
amine functions can also be converted with appropriately activated
or, where appropriate, N-protected enantiopure amino acids into the
corresponding esters or amides, or conversely chiral carboxylic
acids can be converted with carboxyl-protected enantiopure amino
acids into the amides or with enantiopure hydroxy carboxylic acids
such as lactic acid into the corresponding chiral esters. The
chirality of the amino acid or alcohol residue introduced in
enantiopure form can then be utilized for separating the isomers by
carrying out a separation of the diastereomers which are now
present by crystallization or chromatography on suitable stationary
phases, and then eliminating the included chiral moiety by suitable
methods.
A further possibility with some of the compounds of the invention
is to employ diastereomerically or enantiomerically pure starting
materials to prepare the structures. It is thus possible where
appropriate also to employ other or simplified processes for
purifying the final products. These starting materials have
previously been prepared enantiomerically or diastereomerically
pure by processes known from the literature. This may mean in
particular that in the synthesis of the basic structures either
enantioselective methods are employed, or else a separation of
enantiomers (or diastereomers) is carried out at an early stage of
the synthesis and not just at the stage of the final products. It
is likewise possible to achieve a simplification of the separations
by a two-stage or multistage procedure.
Acidic or basic products of the compound of the formula I may be in
the form of their salts or in free form. Pharmacologically
acceptable salts are preferred, for example alkali metal or
alkaline earth metal salts, or hydrochlorides, hydrobromides,
sulfates, hemisulfates, all possible phosphates, and salts of amino
acids, natural bases or carboxylic acids.
Physiologically tolerated salts are prepared from compounds of the
formula I which are capable of salt formation, including their
stereoisomeric forms, by method step d) in a manner known per se.
The compounds of the formula I form stable alkali metal, alkaline
earth metal or optionally substituted ammonium salts with basic
reagents such as hydroxides, carbonates, bicarbonates, alcoholates,
and ammonia or organic bases, for example trimethyl- or
triethylamine, ethanolamine, diethanolamine or triethanolamine,
trometamol or else basic amino acids, for instance lysine,
ornithine or arginine. Where the compounds of the formula I have
basic groups, stable acid addition salts can also be prepared with
strong acids. Suitable for this purpose are both inorganic and
organic acids such as hydrochloric, hydrobromic, sulfuric,
hemisulfuric, phosphoric, methanesulfonic, benzenesulfonic,
p-toluenesulfonic, 4-bromobenzenesulfonic, cyclohexylamidosulfonic,
trifluoromethylsulfonic, 2-hydroxyethanesulfonic, acetic, oxalic,
tartaric, succinic, glycerolphosphoric, lactic, malic, adipic,
citric, fumaric, maleic, gluconic, glucuronic, palmitic, or
TFA.
The invention also relates to medicaments having an effective
content of at least one compound of the formula I and/or of a
physiologically tolerated salt of the compound of the formula I
and/or an optionally stereoisomeric form of the compound of the
formula I, together with a pharmaceutically suitable and
physiologically tolerated carrier, additive and/or other active
substances and excipients.
Because of the pharmacological properties, the compounds of the
invention are suitable for the selective prophylaxis and therapy of
all disorders in the progression of which an enhanced activity of
metalloproteinases such as aggrecanase or TNF-.alpha. are involved.
These include degenerative joint disorders such as osteoarthroses,
spondyloses, chondrolysis after joint trauma or prolonged joint
immobilization after meniscus or patellar injuries or ligament
tears. They also include connective tissue disorders such as
collagenoses, periodontal disorders, wound-healing disturbances and
chronic disorders of the locomotor system such as inflammatory,
immunologically or metabolism-related acute and chronic
arthritides, arthropathies, myalgias and disturbances of bone
metabolism. The compounds of the formula I are also suitable for
the treatment of ulceration, atherosclerosis and stenoses. The
compounds of the formula I are furthermore suitable for the
treatment of inflammations, cancers, tumor metastasis, cachexia,
anorexia, heart failure and septic shock.
The term "osteoarthrosis" means a disorder which arises chiefly
when there is a disparity between the strain and load capacity of
the individual portions of joints and tissues of joints which is
associated with an increasing destruction of cartilage and is
chiefly not inflammatory. The main features of the pathology are
damage to the articular cartilage such as fraying, demedullation or
hyalinization, followed by reactive changes to the subchondral bone
and capsular alterations.
The term "spondylosis" means an arthrosis of the vertebrae which is
characterized by a non-inflammatory chondrolysis of the vertebrae
and intervertebral disks.
The medicaments of the invention can be administered by oral,
inhalational, rectal or transdermal administration or by
subcutaneous, intraarticular, intraperitoneal or intravenous
injection. Oral administration is preferred.
The invention also relates to a process for producing a medicament
which comprises converting at least one compound of the formula I
with a pharmaceutically suitable and physiologically tolerated
carrier and, where appropriate, further suitable active substances,
additives or excipients into a suitable dosage form.
Examples of suitable solid or pharmaceutical preparations are
granules, powders, coated tablets, tablets, (micro)capsules,
suppositories, syrups, oral solutions, suspensions, emulsions,
drops or injectable solutions, and products with protracted release
of active substance, in the production of which conventional aids
such as carriers, disintegrants, binders, coating agents, swelling
agents, glidants or lubricants, flavorings, sweeteners and
solubilizers are used. Excipients which are frequently used and may
be mentioned are magnesium carbonate, titanium dioxide, lactose,
mannitol and other sugars, talc, milk protein, gelatin, starch,
cellulose and its derivatives, animal and vegetable oils such as
fish liver oil, sunflower, peanut or sesame oil, polyethylene
glycol and solvents such as, for example, sterile water and
monohydric or polyhydric alcohols such as glycerol.
The pharmaceutical products are preferably produced and
administered in dosage units, each unit comprising as active
ingredient a particular dose of the compound of the invention of
the formula I. In the case of solid dosage units such as tablets,
capsules, coated tablets or suppositories, this dose can be up to
about 1000 mg, but preferably about 50 to 300 mg, and in the case
of solutions or injection in ampoule form up to about 300 mg, but
preferably about 10 to 100 mg.
The daily doses indicated for the treatment of an adult patient
weighing about 70 kg are from about 20 mg to 1000 mg of active
substance, preferably about 100 mg to 500 mg, depending on the
activity of the compound of the formula I. However, in some
circumstances, higher or lower daily doses may also be appropriate.
The daily dose may be administered both by administration once a
day in the form of a single dosage unit or else a plurality of
smaller dosage units, and by administration more than once a day in
divided doses at defined intervals.
Products are usually characterized by mass spectroscopic methods
(FAB-, ESI-MS), with the main peak or the two main peaks being
indicated in each case, and by their retention time (R.sub.t) in
LC/MS (the method used is noted in each case). Temperatures are
stated in degrees Celsius, RT means room temperature (22.degree. C.
to 26.degree. C.). Abbreviations used are either explained or
correspond to the usual conventions.
The invention is explained in detail below by means of
examples.
EXAMPLES
##STR00010##
1.1 1-(4-Benzyloxybenzyl)imidazolidin-2-one (3)
Imidazolidin-2-one (2.0 g; 23.23 mmol) was dissolved in dimethyl
sulfoxide (DMSO; 30 ml). Potassium carbonate (3.10 g; 23.23 mmol),
potassium iodide (0.95 g; 5.80 mmol) and 4-benzyloxybenzyl chloride
(5.4 g; 23.23 mmol) were added thereto. The mixture was heated at
100.degree. C. for 3 hours (h). Cooling to RT was followed by
partition between water (100 ml) and ethyl acetate (EtOAc, 100 ml).
The phases were separated and the aqueous phase was extracted with
EtOAc (3.times.; 30 ml). The combined organic phases were washed
with saturated NaCl solution (80 ml) and dried over MgSO.sub.4. The
solvent was removed under reduced pressure in a rotary evaporator.
Trituration of the residue with EtOAc (10 ml) triturated resulted
in 1-(4-benzyloxybenzyl)-imidazolidin-2-one (2.10 g; 7.43 mmol).
MS: 283.15 (M+H); R.sub.t: 1.38 min (method: gradient 0 min 90%
H.sub.2O (0.05% TFA) 1.9 min 95% acetonitrile, 95% acetonitrile to
2.4 min, 10% acetonitrile 2.45 min; flow rate 1 ml/min; column 0.4
.mu.L (YMC J'sphere ODS H80 20X2 1.4.mu.); 30.degree. C.)
1.2 Ethyl
2-(3-(4-benzyloxybenzyl)-2-oxoimidazolidin-1-yl)-3-methylbutyrat- e
(5)
1-(4-Benzyloxybenzyl)imidazolidin-2-one (1.0 g; 3.54 mmol) was
dissolved in dimethylformamide (DMF, 10 ml). NaH (60% in mineral
oil; 0.085 g; 3.54 mol) was added, and the mixture was heated at
40.degree. C. for 1 h. Then ethyl 2-bromoisovalerate (0.74 g; 3.54
mmol) were added, and heating was continued at 60.degree. C. for 4
h. The reaction was stopped by slow addition of water (1 ml). The
solvent was removed under reduced pressure, and the residue was
partitioned between water (50 ml) and EtOAc (50 ml). Dilute HCl was
added until the pH of the aqueous phase was about 4. The phases
were then separated, and the aqueous phase was extracted with EtOAc
(2.times.; 30 ml). The combined organic phases were dried over
MgSO.sub.4. The solvent was removed under reduced pressure.
Purification of the residue by column chromatography on silica gel
(SiO.sub.2) resulted in ethyl
2-(3-(4-benzyloxybenzyl)-2-oxoimidazolidin-1-yl)-3-methylbutyrate
(0.38 g; 0.92 mmol). MS: 411.15 (M+H); R.sub.t: 1.87 min (method:
gradient 0 min 90% H.sub.2O (0.05% TFA) 1.9 min 95% acetonitrile,
95% acetonitrile to 2.4 min, 10% acetonitrile 2.45 min; flow rate 1
ml/min; column 0.4 .mu.L (YMC J'sphere ODS H80 20X2 1.4.mu.);
30.degree. C.)
1.3
2-(3-(4-Benzyloxybenzyl)-2-oxoimidazolidin-1-yl)-3-methylbutyric
acid (6)
Ethyl
2-(3-(4-benzyloxybenzyl)-2-oxoimidazolidin-1-yl)-3-methylbutyrate
(0.330 g; 0.80 mmol) was dissolved in methanol (MeOH; 6 ml). NaOH
solution (1N; 3 ml) as added, and the mixture was stirred at RT for
3 h. The solvent was removed under reduced pressure, and saturated
NaH.sub.2PO.sub.4 solution (2 ml) was added to he residue. The
solid was filtered off with suction and dried under reduced
pressure at 60.degree. C. to result in
2-(3-(4-benzyloxybenzyl)-2-oxoimidazolidin-1-yl)-3-methylbutyric
acid (0.25 g; 0.66 mmol). MS: 383.10 (M+H); R.sub.t: 1.57 min
(method: gradient 0 min 90% H.sub.2O (0.05% TFA) 1.9 min 95%
acetonitrile, 95% acetonitrile to 2.4 min, 10% acetonitrile 2.45
min; flow rate 1 ml/min; column 0.4 .mu.L (YMC J'sphere ODS H80
20X2 1.4.mu.); 30.degree. C.)
1.4
2-(3-(4-Benzyloxybenzyl)-2-oxoimidazolidin-1-yl)-N-hydroxy-3-methylbut-
yramide (7)
2-(3-(4-Benzyloxybenzyl)-2-oxoimidazolidin-1-yl)-3-methylbutyric
acid (50 mg; 0.13 mmol) was dissolved in tetrahydrofuran (THF; 2
ml). At 0.degree. C., diisopropylethylamine (DIEA; 69 .mu.l; 0.39
mmol) and ethyl chloroformate (25 .mu.l; 0.26 mmol) were
successively added. The mixture was allowed to reach RT from
0.degree. C. over the course of 2 h, and then
O-trimethylsilylhydroxylamine (50 .mu.l; 0.65 mmol) was added.
Stirring at RT for a further 3 h was followed by partitioning
between dilute HCl (10 ml) and EtOAc (10 ml). The phases were
separated and the aqueous phase was extracted with EtOAc (3.times.;
5 ml). The combined organic phases were dried over MgSO.sub.4. The
solvent was removed under reduced pressure. Trituration of the
residue with EtOAc (2 ml) resulted in
2-(3-(4-benzyloxybenzyl)-2-oxoimidazolidin-1-yl)-N-hydroxy-3-methylbut-
yramide (25 mg; 0.06 mmol). MS: 398.15 (M+H); R.sub.t: 1.30 min
(method: gradient 0 min 96% H.sub.2O (0.05% TFA) 2.0 min 95%
acetonitrile, 95% acetonitrile to 2.4 min, 4% acetonitrile 2.45
min; flow rate 1 ml/min; column 0.4 .mu.L (YMC J'sphere ODS H80
20X2 1.4.mu.); 30.degree. C.)
##STR00011##
2.1 N-1-(4-Benzyloxyphenyl)ethane-1,2-diamine hydrochloride
(10)
4-Benzyloxyaniline hydrochloride (10.0 g; 42.42 mmol) was dissolved
in diethylene glycol monomethyl ether (40 ml). 2-Oxazolidone (4.43
g; 50.90 mmol) was added thereto, and the mixture was heated at
180.degree. C. for 6 h. After cooling to RT, the solid was filtered
off with suction. Washing with diethyl ether (Et.sub.2O) resulted
in N-1-(4-benzyloxyphenyl)ethane-1,2-diamine hydrochloride (3.50 g;
12.55 mmol). MS: 243.15 (M.sub.free base+H); R.sub.t: 0.96 min
(method: gradient 0 min 90% H.sub.2O (0.05% TFA) 1.9 min 95%
acetonitrile, 95% acetonitrile to 2.4 min, 10% acetonitrile 2.45
min; flow rate 1 ml/min; column 0.4 .mu.L (YMC J'sphere ODS H80
20X2 1.4.mu.); 30.degree. C.)
2.2 Ethyl 2-(2-(4-benzyloxyphenylamino)ethylamino)-3-methylbutyrate
(11)
N-1-(4-Benzyloxyphenyl)ethane-1,2-diamine hydrochloride (1.7 g;
6.09 mmol) was dissolved in DMF (15 ml). The solution was heated to
50.degree. C., and triethylamine (NEt.sub.3; 2.55 ml) was added
thereto. Then ethyl-2-bromoisovalerate (1.66 g; 7.92 mmol) was
added and the mixture was heated at 100.degree. C. for 3 h. The
solvent was removed under reduced pressure. Purification of the
residue by column chromatography (SiO.sub.2) resulted in ethyl
2-(2-(4-benzyloxyphenylamino)ethylamino)-3-methylbutyrate (0.30 g;
0.809 mmol). MS: 371.20 (M+H); R.sub.t: 1.29 min (method: gradient
0 min 90% H.sub.2O (0.05% TFA) 1.9 min 95% acetonitrile, 95%
acetonitrile to 2.4 min, 10% acetonitrile 2.45 min; column 0.4
.mu.L (YMC J'sphere ODS H80 20X2 1.4.mu.); 30.degree. C.)
2.3 Ethyl
2-(3-(4-benzyloxyphenyl)-2-oxoimidazolidin-1-yl)-3-methylbutyrat- e
(12)
Ethyl 2-(2-(4-benzyloxyphenylamino)ethylamino)-3-methylbutyrate
(100 mg; 0.27 mmol) was dissolved in toluene (5 ml) and cooled to
0.degree. C. DIEA (141 .mu.l; 0.81 mmol) and phosgene (20% strength
in toluene; 202 .mu.l; 0.40 mmol) were added thereto. The mixture
was allowed to reach RT over the course of 3 h, and then the
solvent was removed under reduced pressure. The residue was
partitioned between water (10 ml) and EtOAc (10 ml). The phases
were separated and the aqueous phase was extracted with EtOAc
(2.times.; 5 ml). The combined organic phases were dried over
MgSO.sub.4. After removal of the solvent whilst under reduced
pressure, ethyl
2-(3-(4-benzyloxyphenyl)-2-oxoimidazolidin-1-yl)-3-methylbutyrate
(90 mg; 0.22 mmol) was obtained. MS: 397.15 (M+H); R.sub.t: 1.90
min (method: gradient 0 min 90% H.sub.2O (0.05% TFA) 1.9 min 95%
acetonitrile, 95% acetonitrile to 2.4 min, 10% acetonitrile 2.45
min; flow rate 1 ml/min; column 0.4 .mu.L (YMC J'sphere ODS H80
20X2 1.4.mu.); 30.degree. C.)
2.4
2-(3-(4-Benzyloxyphenyl)-2-oxoimidazolidin-1-yl)-3-methylbutyric
acid (13)
Ethyl
2-(3-(4-benzyloxyphenyl)-2-oxoimidazolidin-1-yl)-3-methylbutyrate
(110 mg; 0.27 mmol) was dissolved in methanol (3 ml) at 0.degree.
C. Then sodium hydroxide solution (1N, 1.5 ml) was added, and the
reaction mixture was stirred for 4 h during which it was allowed
slowly to reach RT. The methanol was removed in a rotary
evaporator, and the remaining solution was neutralized with
saturated NaH.sub.2PO.sub.4 solution. The precipitated
2-(3-(4-benzyloxyphenyl)-2-oxoimidazolidin-1-yl)-3-methylbutyric
acid (91 mg, 0.25 mmol) was filtered off with suction. MS: 369.20
(M+H); R.sub.t: 1.58 min (method: gradient 0 min 90% H.sub.2O
(0.05% TFA) 1.9 min 95% acetonitrile, 95% acetonitrile to 2.4 min,
10% acetonitrile 2.45 min; flow rate 1 ml/min; column 0.4 .mu.L
(YMC J'sphere ODS H80 20X2 1.4.mu.); 30.degree. C.)
2.5
2-(3-(4-Benzyloxyphenyl)-2-oxoimidazolidin-1-yl)-N-hydroxy-3-methylbut-
yramide (14)
2-(3-(4-Benzyloxyphenyl)-2-oxoimidazolidin-1-yl)-3-methylbutyric
acid (66 mg; 0.18 mmol) was dissolved in THF (2 ml). At 0.degree.
C., diisopropylethylamine (DIEA; 124 .mu.l; 0.71 mmol) and ethyl
chloroformate (51 .mu.l; 0.53 mmol) were successively added. The
mixture was allowed to reach RT from 0.degree. C. over the course
of 2 h and then O-trimethylsilylhydroxylamine (80.43 .mu.l; 1.07
mmol) was added. Stirring at RT for a further 3 h was followed by
partitioning between dilute HCl (10 ml) and EtOAc (10 ml). The
phases were separated and the aqueous phase was extracted with
EtOAc (3.times.; 5 ml). The combined organic phases were dried over
MgSO.sub.4. The solvent was removed under reduced pressure.
Trituration of the residue with EtOAc (2 ml) resulted in
2-(3-(4-benzyloxyphenyl)-2-oxoimidazolidin-1-yl)-N-hydroxy-3-methylbut-
yramide (22 mg; 0.06 mmol). MS: 384.25 (M+H); R.sub.t: 1.94 min
(method: gradient acetonitrile+0.08% formic acid: H.sub.2O+0.1%
formic acid from 5:95 (0 min) to 95:5 (2.5 min) to 95:5 (3 min);
flow rate 1.3 ml/min; column YMC Jsphere 33*2.1)
##STR00012##
3.1 t-Butyl
2-(2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)ethylamino)-3-methylbutyrate
(18)
(R)-Valine t-butyl ester (4.9 g; 28.28 mmol) was dissolved in
methanol (100 ml). Acetic acid (1.62 ml; 28.28 mmol) and
(1,3-dioxo-1,3-dihydroisoindol-2-yl)-acetaldehyde (5.40 g; 28.28
mmol) were added thereto. Then, sodium cyanoborohydride (1.95 g;
31.11 mmol) dissolved in THF (20 ml) was added. The mixture was
stirred at RT for 6 h and then saturated NaHCO.sub.3 solution (200
ml) was added. Methanol was removed under reduced pressure, and the
residue was extracted with EtOAc (3.times.; 100 ml). The combined
organic phases were dried over MgSO.sub.4. Removal of the solvent
under reduced pressure and purification of the residue by column
chromatography (SiO') resulted in t-butyl
(R)-2-(2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)ethylamino)-3-methyl-
butyrate (6.60 g; 19.05 mmol). MS: 347.20 (M+H); R.sub.t: 1.02 min
(method: gradient 0 min 96% H.sub.2O (0.05% TFA) 2.0 min 95%
acetonitrile, 95% acetonitrile to 2.4 min, 4% acetonitrile 2.45
min; flow rate 1 ml/min; column 0.4 .mu.L (YMC J'sphere ODS H80
20X2 1.4.mu.); 30.degree. C.)
3.2 t-Butyl 2-(2-aminoethylamino)-3-methylbutyrate (19)
t-Butyl
(R)-2-(2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)ethylamino)-3-methyl-
butyrate (6.60 g; 19.05 mmol) was dissolved in ethanol (100 ml).
Hydrazine hydrate (4.62 ml; 95.25 mmol) was added, and the reaction
mixture was heated under reflux for 2 h. The solid was filtered off
with suction through kieselguhr and washed with ethanol (100 ml).
The solvent was removed and the residue was partitioned between
saturated NaHCO.sub.3 solution (150 ml) and CH.sub.2Cl.sub.2 (150
ml). The phases were separated and the aqueous phase was extracted
with CH.sub.2Cl.sub.2 (2.times.; 100 ml). The combined organic
phases were dried over MgSO.sub.4. Removal of the solvent under
reduced pressure resulted in t-butyl
(R)-2-(2-aminoethylamino)-3-methylbutyrate (4.60 g; 19.05 mmol).
MS: 217.25 (M+H); R.sub.t: 0.69 min (method: gradient 0 min 96%
H.sub.2O (0.05% TFA) 2.0 min 95% acetonitrile, 95% acetonitrile to
2.4 min, 4% acetonitrile 2.45 min; flow rate 1 ml/min; column 0.4
.mu.L (YMC J'sphere ODS H80 20X2 1.4.mu.); 30.degree. C.)
3.3 t-Butyl
2-(2-(3-benzyloxybenzylamino)ethylamino)-3-methylbutyrate (21)
t-Butyl (R)-2-(2-aminoethylamino)-3-methylbutyrate (100 mg; 0.46
mmol) was dissolved in methanol (2 ml). Acetic acid (8 .mu.l; 0.14
mmol), 3-benzyloxybenzaldehyde (98 mg; 0.46 mmol) and sodium
cyanoborohydride (32 mg; 0.50 mmol) were added. Stirring at RT for
6 h was followed by partitioning between saturated NaHCO.sub.3
solution (8 ml) and CH.sub.2Cl.sub.2 (8 ml). The phases were
separated, and the aqueous phase was extracted with
CH.sub.2Cl.sub.2 (2.times.; 5 ml). The combined organic phases were
dried over MgSO.sub.4, and the solvent was removed under reduced
pressure. Purification by preparative HPLC afforded t-butyl
(R)-2-(2-(3-benzyloxybenzylamino)ethylamine)-3-methylbutyrate (155
mg; 0.37 mmol) MS: 413.25 (M+H); R.sub.t: 1.11 min (method:
gradient 0 min 96% H.sub.2O (0.05% TFA) 2.0 min 95% acetonitrile,
95% acetonitrile to 2.4 min, 4% acetonitrile 2.45 min; column 0.4
.mu.L (YMC J'sphere ODS H80 20X2 1.4.mu.); 30.degree. C.)
3.4 t-Butyl
2-(3-(3-benzyloxybenzyl)-2-oxoimidazolidin-1-yl)-3-methylbutyrate
(22)
t-Butyl
(R)-2-(2-(3-benzyloxybenzylamino)ethylamino)-3-methylbutyrate (155
mg; 0.37 mmol) was dissolved in toluene (5 ml) and cooled to
0.degree. C. NaOH (1N; 5 ml; 5 mmol) was added, as was phosgene
(20% in toluene; 0.37 ml; 0.75 mmol). The mixture was stirred at
0.degree. C. for 6 h, the phases were separated, and the aqueous
phase was extracted with CH.sub.2Cl.sub.2 (2.times.; 5 ml). The
combined organic phases were dried over MgSO.sub.4, and the
solvents were removed under reduced pressure. Purification of the
residue by column chromatography (SiO.sub.2) resulted in t-butyl
(R)-2-(3-(3-benzyloxybenzyl)-2-oxoimidazolidin-1-yl)-3-methylbutyrate
(102 mg; 0.23 mmol). MS: 439.25 (M+H); R.sub.t: 2.12 min (method:
gradient 0 min 96% H.sub.2O (0.05% TFA) 2.0 min 95% acetonitrile,
95% acetonitrile to 2.4 min, 4% acetonitrile 2.45 min; flow rate 1
ml/min; column 0.4 .mu.L (YMC J'sphere ODS H80 20X2 1.4.mu.);
30.degree. C.)
3.5
2-(3-(3-Benzyloxybenzyl)-2-oxoimidazolidin-1-yl)-N-hydroxy-3-methylbut-
yramide (24)
t-Butyl
(R)-2-(3-(3-benzyloxybenzyl)-2-oxoimidazolidin-1-yl)-3-methylbuty-
rate (102 mg; 0.23 mmol) was dissolved in CH.sub.2Cl.sub.2 (2 ml)
and cooled to 0.degree. C. Trifluoroacetic acid (TFA; 1 ml) was
added, and the mixture was stirred for 2 h. The solvents were
removed under reduced pressure, and the residue was taken up in
tetrahydrofuran (THF; 2 ml). DIEA (0.16 ml; 0.93 mmol) and ethyl
chloroformate (67 .mu.l; 0.69 mmol) were added. After stirring at
RT for 2 h, O-trimethylsilylhydroxylamine (0.10 ml; 1.39 mmol) was
added. The mixture was stirred for 15 h, HCl (6N, 0.30 ml) was
added, and then the solvents were removed under reduced pressure.
Purification of the residue by preparative HPLC resulted in
(R)-2-(3-(3-benzyloxybenzyl)-2-oxoimidazolidin-1-yl)-N-hydroxy-3-methylbu-
tyramide (8 mg, 0.02 mmol). MS: 398.15 (M+H); R.sub.t: 1.46 min
(method: gradient 0 min 96% H.sub.2O (0.05% TFA) 2.0 min 95%
acetonitrile, 95% acetonitrile to 2.4 min, 4% acetonitrile 2.45
min; flow rate 1 ml/min; column 0.4 .mu.L (YMC J'sphere ODS H80
20X2 1.4.mu.); 30.degree. C.)
##STR00013##
4.1 2-Hydroxy-1-(4-methoxyphenyl)ethanone (26)
4-Methoxyacetophenone (10 g; 66.59 mmol) was added to a solution of
acetonitrile (350 ml), water (70 ml) and trifluoroacetic acid (TFA)
(10.26 ml; 133.20 mmol). Then (bis(trifluoroacetoxy)iodo)benzene
was added, and the reaction mixture was heated under reflux for 3
h. The acetonitrile was then stripped off in a rotary evaporator,
and the reaction mixture was partitioned in NaHCO.sub.3
solution/CH.sub.2Cl.sub.2. After extraction with CH.sub.2Cl.sub.2
(2.times.), the combined organic phases were dried over MgSO.sub.4,
and the solvent was removed in a rotary evaporator. Purification by
column chromatography (CH.sub.2Cl.sub.2/MeOH 50:1) resulted in
2-hydroxy-1-(4-methoxyphenyl)ethanone (6.0 g; 36.1 mmol). MS:
167.15 (M+H); R.sub.t: 0.83 min (method: gradient 0 min 96%
H.sub.2O (0.05% TFA) 2.0 min 95% acetonitrile, 95% acetonitrile to
2.4 min, 4% acetonitrile 2.45 min; flow rate 1 ml/min; column 0.4
.mu.L (YMC J'sphere ODS H80 20X2 1.4.mu.); 30.degree. C.)
4.2 t-Butyl
2-(2-hydroxy-1-(4-methoxyphenyl)ethylamino)-3-methylbutyrate
(27)
Valine t-butyl ester hydrochloride (3.85 g; 18.38 mmol) was
partitioned in 1N NaOH/CH.sub.2Cl.sub.2 and extracted with
CH.sub.2Cl.sub.2 (2.times.), and the combined organic phases were
dried over MgSO.sub.4. After concentration in a rotary evaporator,
the free amine obtained in this way was taken up in
1,2-dichloroethane (30 ml). Then,
2-hydroxy-1-(4-methoxyphenyl)ethanone (2.35 g; 14.14 mmol) and
acetic acid (0.48 ml; 8.48 mmol) were added. The mixture was
stirred at RT for 1 h and then NaBH(OAc).sub.3 (3.89 g; 18.38 mmol)
was added, and stirring was continued at RT for 4 h. The reaction
mixture was partitioned in NaHCO.sub.3 solution/CH.sub.2Cl.sub.2
and extracted with CH.sub.2Cl.sub.2 (2.times.). The combined
organic phases were dried over MgSO.sub.4, and the solvent was
removed in a rotary evaporator. Purification by chromatography
resulted in t-butyl
2-(2-hydroxy-1-(4-methoxyphenyl)-ethylamino)-3-methylbutyrate (2.5
g; 7.73 mmol). MS: 324.20 (M+H); R.sub.t: 1.07 min (method:
gradient 0 min 96% H.sub.2O (0.05% TFA) 2.0 min 95% acetonitrile,
95% acetonitrile to 2.4 min, 4% acetonitrile 2.45 min; flow rate 1
ml/min; column 0.4 .mu.L (YMC J'sphere ODS H80 20X2 1.4.mu.);
30.degree. C.)
4.3 t-Butyl
2-(4-(4-methoxyphenyl)-2,2-dioxo-(1,2,3)oxathiazolidin-3-yl)-3-methylbuty-
rate (28)
t-Butyl
2-(2-hydroxy-1-(4-methoxyphenyl)ethylamino)-3-methylbutyrate (2.5
g; 7.73 mmol) was introduced into CH.sub.2Cl.sub.2 (200 ml), and
the solution was cooled to -78.degree. C. Addition of pyridine
(3.12 ml; 38.65 mmol) was followed by slow dropwise addition of
thionyl chloride (0.67 ml; 9.27 mmol). The reaction mixture was
stirred for 1 h, during which the temperature was allowed to rise
to 0.degree. C. The reaction mixture was partitioned between
aqueous 1% strength HCl/CH.sub.2Cl.sub.2 and extracted with
CH.sub.2Cl.sub.2 (2.times.). The combined organic phases were
washed with saturated NaHCO.sub.3 solution and dried over
MgSO.sub.4, and the solvent was removed in a rotary evaporator. The
residue was taken up in acetonitrile (20 ml) and cooled to
0.degree. C. Then NaIO.sub.4 (1.82 g; 8.5 mmol),
RuCl.sub.3.H.sub.2O (14.43 mg; 0.077 mmol) and water (20 ml) were
added. The reaction mixture was stirred at 0.degree. C. for 5
minutes and then at RT for a further 20 minutes. It was then
partitioned between saturated NaHCO.sub.3 solution/CH.sub.2Cl.sub.2
and extracted with CH.sub.2Cl.sub.2 (2.times.). The combined
organic phases were washed with saturated NaHCO.sub.3 and dried
over MgSO.sub.4, and the solvent was removed in a rotary
evaporator. Purification by chromatography resulted in t-butyl
2-(4-(4-methoxyphenyl)-2,2-dioxo-(1,2,3)oxathiazolidin-3-yl)-3-methylbuty-
rate (2.5 g; 6.48 mmol). MS: 403.15 (M+NH.sub.4.sup.+); R.sub.t:
1.82 min (method: gradient 0 min 96% H.sub.2O (0.05% TFA) 2.0 min
95% acetonitrile, 95% acetonitrile to 2.4 min, 4% acetonitrile 2.45
min; flow rate 1 ml/min; column 0.4 .mu.L (YMC J'sphere ODS H80
20X2 1.4.mu.); 30.degree. C.).
4.4
2-(3-Benzyl-5-(4-methoxyphenyl)-2-oxoimidazolidin-1-yl)-3-methylbutyri-
c acid (29)
t-Butyl 2-(4-(4-methoxyphenyl)-2,2-dioxo-(1,2,3)
oxathiazolidin-3-yl)-3-methylbutyrate (0.30 g; 0.778 mmol) was
introduced into acetonitrile (5 ml). Benzylamine (0.10 g; 0.93
mmol) and Cs.sub.2CO.sub.3 (0.50 g; 1.55 mmol) were added thereto,
and the reaction mixture was stirred at 55.degree. C. for 5 h. It
was then filtered through kieselguhr, and the residue was washed
with a solution of methanol (3%) in acetonitrile. The filtrate was
concentrated in a rotary evaporator, and the residue was taken up
in dioxane (10 ml) and concentrated aqueous H.sub.2SO.sub.4 (10
ml). The mixture was stirred at 70.degree. C. for 2 h and then
evaporated to dryness in a rotary evaporator. The residue was taken
up in toluene, and 1N NaOH (10 ml) was added. After the reaction
mixture had been cooled to 0.degree. C., phosgene (20% in toluene;
0.58 ml; 1.16 mmol) was slowly added dropwise. The mixture was then
stirred at 0.degree. C. for 2 h. The reaction mixture was adjusted
to pH 1-2 with dilute aqueous HCl, mixed with EtOAc and extracted
with EtOAc (2.times.). The combined organic phases were dried over
MgSO.sub.4, and the solvent was removed in a rotary evaporator.
Purification by column chromatography (CH.sub.2Cl.sub.2/MeOH,
gradient) resulted in
2-(3-benzyl-5-(4-methoxyphenyl)-2-oxoimidazolidin-1-yl)-3-methylbutyric
acid (0.15 g; 0.39 mmol). MS: 383.15 (M+H); R.sub.t: 1.52 min
(method: gradient 0 min 96% H.sub.2O (0.05% TFA) 2.0 min 95%
acetonitrile, 95% acetonitrile to 2.4 min, 4% acetonitrile 2.45
min; flow rate 1 ml/min; column 0.4 .mu.L (YMC J'sphere ODS H80
20X2 1.4.mu.); 30.degree. C.)
4.5
2-(3-Benzyl-5-(4-methoxyphenyl)-2-oxoimidazolidin-1-yl)-N-benzyloxy-3--
methylbutyramide (30)
2-(3-Benzyl-5-(4-methoxyphenyl)-2-oxoimidazolidin-1-yl)-3-methylbutyric
acid (150 mg; 0.39 mmol) was introduced into DMF (10 ml) and cooled
to 0.degree. C. Then N,N-diisopropylethylamine (202 mg; 1.56 mmol),
O-benzylhydroxylamine hydrochloride (125 mg, 0.78 mmol) and
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (HATU; 223 mg; 0.58 mmol) were added, and the
mixture was stirred at 0.degree. C. for 2 h. The reaction solution
was then concentrated and partitioned between dilute HCl
solution/EtOAc and extracted with EtOAc (2.times.). The combined
organic phases were dried over MgSO.sub.4, and the solvent was
removed in a rotary evaporator. Purification by chromatography
resulted in
2-(3-benzyl-5-(4-methoxyphenyl)-2-oxoimidazolidin-1-yl)-N-benzyloxy-3-met-
hylbutyramide (116 mg; 0.24 mmol). MS: 488.25 (M+H); R.sub.t: 3.50
min (method: gradient 95% H.sub.2O (0.05% TFA) to 95% acetonitrile
over 3.5 min, 95% acetonitrile for 1.0 min, 5% acetonitrile 1.0
min; flow rate 0.5 ml/min; column 1 .mu.L (Merck Purospher 5.mu.
2.times.55 mm); 30.degree. C.)
4.6
2-(3-Benzyl-5-(4-methoxyphenyl)-2-oxoimidazolidin-1-yl)-N-hydroxy-3-me-
thylbutyramide (31)
2-(3-Benzyl-5-(4-methoxyphenyl)-2-oxoimidazolidin-1-yl)-N-benzyloxy-3-met-
hylbutyramide (120 mg; 0.24 mmol) was introduced into methanol (10
ml), and Pd/BaSO.sub.4 (50 mg) was added. The mixture was
hydrogenated with H.sub.2 (1 atm) at RT for 4 h. The reaction
mixture was then filtered through kieselguhr, the residue was
washed with methanol, and the filtrate was concentrated in a rotary
evaporator. Purification by preparative HPLC resulted in
2-(3-benzyl-5-(4-methoxyphenyl)-2-oxoimidazolidin-1-yl)-N-hydroxy-3-methy-
lbutyramide (60 mg, 0.15 mmol). MS: 398.15 (M+H); R.sub.t: 1.31 min
(method: gradient 0 min 96% H.sub.2O (0.05% TFA) 2.0 min 95%
acetonitrile, 95% acetonitrile to 2.4 min, 4% acetonitrile 2.45
min; flow rate 1 ml/min; column 0.4 .mu.L (YMC J'sphere ODS H80
20X2 1.4.mu.); 30.degree. C.)
##STR00014##
5.1 Ethyl
2-(3-(4-hydroxybenzyl)-2-oxoimidazolidin-1-yl)-3-methylbutyrate
(32)
Ethyl
2-(3-(4-benzyloxybenzyl)-2-oxoimidazolidin-1-yl)-3-methylbutyrate
(400 mg; 0.97 mmol) was dissolved in ethanol (20 ml). Pd(OH).sub.2
(100 mg; 0.71 mmol) was added thereto, and hydrogenation was
carried out under about 1 atm. of hydrogen for 3 h. The catalyst
was filtered off through kieselguhr and washed with ethanol
(2.times.; 20 ml). The solvent was removed under reduced pressure.
Purification of the residue by column chromatography (SiO.sub.2)
resulted in ethyl
2-(3-(4-hydroxybenzyl)-2-oxoimidazolidin-1-yl)-3-methylbutyrate
(300 mg; 0.94 mmol). MS: 321.35 (M+H); R.sub.t: 1.24 min (method:
gradient 0 min 96% H.sub.2O (0.05% TFA) 2.0 min 95% acetonitrile,
95% acetonitrile to 2.4 min, 4% acetonitrile 2.45 min; flow rate 1
ml/min; column 0.4 .mu.L (YMC J'sphere ODS H80 20X2 1.4.mu.);
30.degree. C.)
5.2 Ethyl
3-methyl-2-{2-oxo-3-(4-(pyridin-4-ylmethoxy)benzyl)imidazolidin--
1-yl}-butyrate (33)
Ethyl
2-(3-(4-hydroxybenzyl)-2-oxoimidazolidin-1-yl)-3-methylbutyrate (50
mg; 0.15 mmol) was dissolved in DMSO (1 ml). 4-Chloromethylpyridine
hydrochloride (39 mg; 0.23 mmol), potassium carbonate (86 mg; 0.62
mmol) and potassium iodide (8 mg, 0.4 mmol) were successively added
thereto. The mixture was heated at 50.degree. C. for 3 h. Cooling
to RT was followed by partitioning between water (10 ml) and EtOAc
(10 ml). The phases were separated and the aqueous phase was
extracted with EtOAc (3.times.; 5 ml). The combined organic phases
were dried over MgSO.sub.4, and the solvent was removed under
reduced pressure. Purification of the residue by column
chromatography (SiO.sub.2) resulted in ethyl
3-methyl-2-{2-oxo-3-(4-(pyridin-4-ylmethoxy)benzyl)imidazolidin-1-yl}-but-
yrate (45 mg; 0.11 mmol). MS: 412.50 (M+H); R.sub.t: 1.04 min
(method: gradient 0 min 96% H.sub.2O (0.05% TFA) 2.0 min 95%
acetonitrile, 95% acetonitrile to 2.4 min, 4% acetonitrile 2.45
min; flow rate 1 ml/min; column 0.4 .mu.L (YMC J'sphere ODS H80
20X2 1.4.mu.); 30.degree. C.)
5.3
3-Methyl-2-{2-oxo-3-(4-(pyridin-4-ylmethoxy)benzyl)imidazolidin-1-yl}--
butyric acid (34)
Ethyl
3-methyl-2-{2-oxo-3-(4-(pyridin-4-ylmethoxy)benzyl)imidazolidin-1-y-
l}-butyrate (45 mg; 0.11 mmol) was dissolved in methanol (1.5 ml)
and cooled to 0.degree. C. NaOH (1N, 5 ml) was added, and the
mixture was allowed to warm to RT over the course of 3 h. The
methanol was then removed under reduced pressure, and water (1.5
ml) and saturated NaH.sub.2PO.sub.4 solution (3 ml) were added to
the residue. The solid was filtered off with suction and washed
with water. Drying under reduced pressure at 60.degree. C. resulted
in
3-methyl-2-{2-oxo-3-(4-(pyridin-4-ylmethoxy)benzyl)imidazolidin-1-yl}-but-
yric acid (36 mg; 0.09 mmol). MS: 384.45 (M+H); R.sub.t: 0.87 min
(method: gradient 0 min 96% H.sub.2O (0.05% TFA) 2.0 min 95%
acetonitrile, 95% acetonitrile to 2.4 min, 4% acetonitrile 2.45
min; flow rate 1 ml/min; column 0.4 .mu.L (YMC J'sphere ODS H80
20X2 1.4.mu.); 30.degree. C.)
5.4
N-Hydroxy-3-methyl-2-[2-oxo-3-(4-(pyridin-4-ylmethoxy)benzyl)-imidazol-
idin-1-yl]butyramide; compound with TFA (35)
3-Methyl-2-{2-oxo-3-(4-(pyridin-4-ylmethoxy)benzyl)imidazolidin-1-yl}buty-
ric acid (36 mg; 0.09 mmol) were dissolved in THF (5 ml) and cooled
to 0.degree. C. DIEA (66 .mu.l; 0.37 mmol) and ethyl chloroformate
(27 .mu.l; 0.28 mmol) were successively added thereto. The mixture
was allowed to reach RT over the course of 3 h. Then
O-(trimethylsilyl)hydroxylamine 42 .mu.l; 0.56 mmol) was added, and
stirring was continued at RT for 15 h. The solvent was then removed
under reduced pressure. The residue was taken up in dilute HCl (2
ml) and stirred for 10 min. The mixture was neutralized with dilute
NaOH and extracted with CHCl.sub.3/i-propanol (4:1; 3.times.; 10
ml). The combined organic phases were dried over MgSO.sub.4, and
the solvent was removed under reduced pressure. Purification of the
residue by preparative HPLC purified resulted in
N-hydroxy-3-methyl-2-{2-oxo-3-(4-(pyridin-4-ylmethoxy)benzyl)imidazolidin-
-1-yl}butyramide as trifluoroacetate (9 mg; 0.02 mmol). MS: 399.40
(M+H); R.sub.t: 0.78 min (method: gradient 0 min 96% H.sub.2O
(0.05% TFA) 2.0 min 95% acetonitrile, 95% acetonitrile to 2.4 min,
4% acetonitrile 2.45 min; flow rate 1 ml/min; column 0.4 .mu.L (YMC
J'sphere ODS H80 20X2 1.4.mu.); 30.degree. C.)
##STR00015##
6.1 1-Hydroxy-3-(4-methoxyphenyl)propan-2-one (37)
4-Allylanisole (98%; 3.0 g; 19.86 mmol) was dissolved in glacial
acetic acid (180 ml), water (180 ml) and acetone (180 ml).
KMnO.sub.4 (4.7 g; 29.79 mmol) was added over the course of 1 h.
The mixture was then stirred at (RT) for 1 h. It was then
decolorized with saturated NaHCO.sub.3 solution. The reaction
volume was reduced in a rotary evaporator. This was followed by
extraction with CH.sub.2Cl.sub.2, washing of the organic phase with
water and drying over Na.sub.2SO.sub.4. The solvent was then
removed in a rotary evaporator. The oily residue was purified by
column chromatography (SiO.sub.2; EtOAc/n-heptane 1:2).
1-Hydroxy-3-(4-methoxyphenyl)propan-2-one was obtained as a white
crystalline powder. MS: 81.20 (M+H); R.sub.t: 0.83 min (method:
gradient 0 min 96% H.sub.2O (0.05% TFA) 2.0 min 95% acetonitrile,
95% acetonitrile to 2.4 min, 4% acetonitrile 2.45 min; flow rate 1
ml/min; column 0.4 .mu.L (YMC J'sphere ODS H80 20X2 1.4.mu.);
30.degree. C.)
6.2 t-Butyl
2-(1-hydroxymethyl-2-(4-methoxyphenyl)ethylamino)-3-methylbutyrate
(38)
Valine t-butyl ester hydrochloride (302 mg; 1.45 mmol) was
dissolved in a little 1N NaOH and extracted with CH.sub.2Cl.sub.2
(3.times.), and the combined organic phases were dried over
Na.sub.2SO.sub.4. After concentration in a rotary evaporator, the
free amine obtained in this way was dissolved in 1,2-dichloroethane
(2.4 ml). Then, 1-hydroxy-3-(4-methoxyphenyl)propan-2-one (200 mg,
1.1 mmol) and glacial acetic acid (38 .mu.l) were added. The
mixture was stirred at RT for 1 h. NaBH(OAc).sub.3 (303 mg; 1.45
mmol) was added. This was followed by stirring at RT for 4 h. The
reaction mixture was taken up in CH.sub.2Cl.sub.2 and washed with
saturated NaHCO.sub.3 solution, and the organic phase was dried
over Na.sub.2SO.sub.4. Concentration in a rotary evaporator
resulted in an oily residue which was purified by preparative HPLC.
The acetonitrile was removed from the combined product fractions in
a rotary evaporator, and saturated NaHCO.sub.3 solution was added.
This was followed by extraction with CH.sub.2Cl.sub.2 and drying
over Na.sub.2SO.sub.4. Concentration in a rotary evaporator
resulted in t-butyl
2-(1-hydroxymethyl-2-(4-methoxyphenyl)-ethylamino)-3-methylbutyra-
te (74 mg; 0.22 mmol). MS: 338.20 (M+H); R.sub.t: 1.05 min (method:
gradient 0 min 96% H.sub.2O (0.05% TFA) 2.0 min 95% acetonitrile,
95% acetonitrile to 2.4 min, 4% acetonitrile 2.45 min; flow rate 1
ml/min; column 0.4 .mu.L (YMC J'sphere ODS H80 20X2 1.4.mu.);
30.degree. C.)
6.3 t-Butyl
2-(4-(4-methoxybenzyl)-2-oxo-(1,2,3)oxathiazolidin-3-yl)-3-methylbutyrate
(39)
t-Butyl
2-(1-hydroxymethyl-2-(4-methoxyphenyl)ethylamino)-3-methylbutyrat-
e (2.49 g; 7.4 mmol) was dissolved in CH.sub.2Cl.sub.2 (180 ml).
The reaction solution was cooled to -78.degree. C. Then pyridine (3
ml; 37 mmol) was added and subsequently thionyl chloride (0.64 ml;
8.88 mmol) was added dropwise. The reaction mixture was stirred for
1 h, during which the temperature was allowed to reach 0.degree. C.
It was taken up in CH.sub.2Cl.sub.2 and washed with aqueous HCl
(1%; 2.times.) and NaHCO.sub.3 solution. The organic phase was
dried over Na.sub.2SO.sub.4 and concentrated in a rotary
evaporator. The crude product was purified by filtration through
silica gel (100 g). t-Butyl
2-(4-(4-methoxybenzyl)-2-oxo-(1,2,3)oxathiazolidin-3-yl)-3-methylbutyrate
(2.35 g; 0.61 mmol) was obtained as a dark yellow oil. MS: 384.20
(M+H); R.sub.t: 1.76 min (method: gradient 0 min 96% H.sub.2O
(0.05% TFA) 2.0 min 95% acetonitrile, 95% acetonitrile to 2.4 min,
4% acetonitrile 2.45 min; flow rate 1 ml/min; column 0.4 .mu.L (YMC
J'sphere ODS H80 20X2 1.4.mu.); 30.degree. C.)
6.4 t-Butyl
2-(4-(4-methoxybenzyl)-2,2-dioxo-(1,2,3)oxathiazolidin-3-yl)-3-methylbuty-
rate (40)
t-Butyl 2-(4-(4-methoxybenzyl)-2-oxo-(1,2,3)
oxathiazolidin-3-yl)-3-methylbutyrate (2.2 g; 5.7 mmol) was
dissolved in acetonitrile (15 ml) and the reaction solution was
cooled to 0.degree. C. Then NaIO.sub.4 (1.47 g; 6.8 mmol),
RuCl.sub.3.H.sub.2O (128.5 mg; 0.57 mmol) and water (15 ml) were
added. The reaction solution was stirred at 0.degree. C. for 5
minutes and then at RT for 30 minutes. This was followed by
addition of NaHCO.sub.3 solution, extraction with CH.sub.2Cl.sub.2
(3.times.) and drying of the organic phase over NaSO.sub.4 and
concentration in a rotary evaporator. The crude product was
filtered through an SiO.sub.2 cartridge (10 g). t-Butyl
2-(4-(4-methoxybenzyl)-2,2-dioxo-(1,2,3)oxathiazolidin-3-yl)-3-methylbuty-
rate (2.02 g; 5.0 mmol) was obtained as a yellow oil. MS: 417.45
(M+NH.sub.4.sup.+); R.sub.t: 1.86 min (method: gradient 0 min 96%
H.sub.2O (0.05% TFA) 2.0 min 95% acetonitrile, 95% acetonitrile to
2.4 min, 4% acetonitrile 2.45 min; flow rate 1 ml/min; column 0.4
.mu.L (YMC J'sphere ODS H80 20X2 1.4.mu.); 30.degree. C.)
6.5 t-Butyl
2-(2-benzylamino-1-(4-methoxybenzyl)ethylamino)-3-methylbutyrate
(41)
t-Butyl 2-(4-(4-methoxybenzyl)-2,2-dioxo-(1,2,3)
oxathiazolidin-3-yl)-3-methylbutyrate (1.0 g; 2.5 mmol) was
dissolved in acetonitrile (15 ml). Cs.sub.2CO.sub.3 (1.63 g; 5
mmol) and benzylamine (0.5 ml; 4.5 mmol) were added, The reaction
mixture was stirred at 55.degree. C. for 4 h. It was then allowed
to reach RT, and the reaction mixture was filtered through a
clarifying layer. The residue was washed with acetonitrile. The
filtrate was concentrated and taken up in CH.sub.2Cl.sub.2 (10 ml).
Aqueous H.sub.2SO.sub.4 (20%; 5 ml) was added, and the mixture was
stirred at RT for 1.5 h. The phases were then separated, the
aqueous phase was extracted with CH.sub.2Cl.sub.2 (2.times.), and
the combined organic phases were dried over Na.sub.2SO.sub.4 and
concentrated in a rotary evaporator. The crude product was stirred
with CH.sub.2Cl.sub.2/CH.sub.3CN/Et.sub.2O and concentrated.
t-Butyl
2-(2-benzylamino-1-(4-methoxybenzyl)ethylamino)-3-methylbutyrate
(1.15 g; 2.5 mmol) was obtained as a yellowish foam. MS: 427.20
(M+H); R.sub.t: 1.42 min (method: gradient 0 min 96% H.sub.2O
(0.05% TFA) 2.0 min 95% acetonitrile, 95% acetonitrile to 2.4 min,
4% acetonitrile 2.45 min; flow rate 1 ml/min; column 0.4 .mu.L (YMC
J'sphere ODS H80 20X2 1.4.mu.); 30.degree. C.)
6.6 t-Butyl
2-(3-benzyl-5-(4-methoxybenzyl)-2-oxoimidazolidin-1-yl)-3-methyl-butyrate
(42)
t-Butyl
2-(2-benzylamino-1-(4-methoxybenzyl)ethylamino)-3-methylbutyrate
(0.64 g; 1.5 mmol) was dissolved in toluene (40 ml). Triethylamine
(457 .mu.L; 3.3 mmol) and triphosgene (0.49 g; 1.65 mmol) were
added. The reaction mixture was stirred at RT for 4.5 h. It was
then washed with water (1.times.), saturated NaHCO.sub.3 solution
(1.times.) and again with water (1.times.). The organic phase was
dried over Na.sub.2SO.sub.4 and concentrated in a rotary
evaporator. The crude product was chromatographed on an SiO.sub.2
cartridge (EtOAc/n-heptane 1:3). t-Butyl
2-(3-benzyl-5-(4-methoxybenzyl)-2-oxoimidazolidin-1-yl)-3-methylbutyrate
(0.22 g, 0.48 mmol) was obtained as a yellow oil. MS: 453.20 (M+H);
R.sub.t: 1.94 min (method: gradient 0 min 96% H.sub.2O (0.05% TFA)
2.0 min 95% acetonitrile, 95% acetonitrile to 2.4 min, 4%
acetonitrile 2.45 min; flow rate 1 ml/min; column 0.4 .mu.L (YMC
J'sphere ODS H80 20X2 1.4.mu.); 30.degree. C.)
6.7
2-(3-Benzyl-5-(4-methoxybenzyl)-2-oxoimidazolidin-1-yl)-3-methylbutyri-
c acid (43)
t-Butyl
2-(3-benzyl-5-(4-methoxybenzyl)-2-oxoimidazolidin-1-yl)-3-methylb-
utyrate (0.22 g; 0.48 mmol) was dissolved in CH.sub.2Cl.sub.2 (2
ml), and the reaction solution was cooled to 0.degree. C. Then TFA
(2 ml) was added. The reaction mixture was stirred at 0.degree. C.
for 3 h. It was then concentrated in a rotary evaporator, and the
residue was taken up with water and extracted with CH.sub.2Cl.sub.2
(3.times.). The organic phase was dried over Na.sub.2SO.sub.4 and
concentrated in a rotary evaporator.
2-(3-Benzyl-5-(4-methoxybenzyl)-2-oxoimidazolidin-1-yl)-3-methylbutyric
acid (0.18 g; 0.45 mmol) was obtained as a yellow oil. MS: 397.20
(M+H); R.sub.t: 1.52 min (method: gradient 0 min 96% H.sub.2O
(0.05% TFA) 2.0 min 95% acetonitrile, 95% acetonitrile to 2.4 min,
4% acetonitrile 2.45 min; flow rate 1 ml/min; column 0.4 .mu.L (YMC
J'sphere ODS H80 20X2 1.4.mu.); 30.degree. C.)
6.8
2-(3-Benzyl-5-(4-methoxybenzyl)-2-oxoimidazolidin-1-yl)-N-hydroxy-3-me-
thylbutyramide (44)
2-(3-Benzyl-5-(4-methoxybenzyl)-2-oxoimidazolidin-1-yl)-3-methylbutyric
acid (174 mg; 0.44 mmol) was dissolved in THF (4 ml). Ethyl
chloroformate (42 .mu.L; 0.53 mmol), N-ethylmorpholine (112 .mu.L;
0.88 mmol) and O-trimethylsilyl-hydroxalanine (90%) were added. The
reaction mixture was stirred at RT for 3 h and then concentrated in
a rotary evaporator. The residue was taken up in CH.sub.2Cl.sub.2
and extracted with H.sub.2O (1.times.), and the organic phase was
dried over Na.sub.2SO.sub.4 and concentrated in a rotary
evaporator. The crude product was purified on an SiO.sub.2
cartridge (50 g) (CH.sub.2Cl.sub.2/MeOH 50:1). Subsequent
crystallization from diethyl ether/n-pentane resulted in
2-(3-benzyl-5-(4-methoxybenzyl)-2-oxoimidazolidin-1-yl)-N-hydroxy-3-methy-
lbutyramide (92 mg; 0.23 mmol) as white crystals. MS: 412.20 (M+H);
R.sub.t: 1.35 min (method: gradient 0 min 96% H.sub.2O (0.05% TFA)
2.0 min 95% acetonitrile, 95% acetonitrile to 2.4 min, 4%
acetonitrile 2.45 min; flow rate 1 ml/min; column 0.4 .mu.L (YMC
J'sphere ODS H80 20X2 1.4.mu.); 30.degree. C.)
Example 1
2-(3-(4-Benzyloxybenzyl)-2-oxoimidazolidin-1-yl)-N-hydroxy-3-methylbutyram-
ide
2-(3-(4-Benzyloxybenzyl)-2-oxoimidazolidin-1-yl)-N-hydroxy-3-methylbutyra-
mide (25 mg) was obtained from imidazolidin-2-one in analogy to the
procedure in 3.1. MS: 398.15 (M+H); R.sub.t: 1.30 min (method:
gradient 0 min 96% H.sub.2O (0.05% TFA) 2.0 min 95% acetonitrile,
95% acetonitrile to 2.4 min, 4% acetonitrile 2.45 min; flow rate 1
ml/min; column 0.4 .mu.L (YMC J'sphere ODS H80 20X2 1.4.mu.);
30.degree. C.)
Example 2
2-(3-(4-Benzyloxyphenyl)-2-oxoimidazolidin-1-yl)-N-hydroxy-3-methylbutyram-
ide
2-(3-(4-Benzyloxyphenyl)-2-oxoimidazolidin-1-yl)-N-hydroxy-3-methylbutyra-
mide (22 mg) was obtained from 2-oxazolidone in analogy to the
procedure in 3.2. MS: 384.25 (M+H); R.sub.t: 1.94 min (method:
gradient acetonitrile+0.08% formic acid: H.sub.2O+0.1% formic acid
from 5:95 (0 min) to 95:5 (2.5 min) to 95:5 (3 min); flow rate 1.3
ml/min; column YMC Jsphere 33*2.1)
Example 3
2-(3-(3-Benzyloxybenzyl)-2-oxoimidazolidin-1-yl)-N-hydroxy-3-methylbutyram-
ide
2-(3-(3-Benzyloxybenzyl)-2-oxoimidazolidin-1-yl)-N-hydroxy-3-methylbutyra-
mide (8 mg) was obtained from valine t-butyl ester hydrochloride in
analogy to the procedure in 3.3. MS: 398.15 (M+H); R.sub.t: 1.46
min (method: gradient 0 min 96% H.sub.2O (0.05% TFA) 2.0 min 95%
acetonitrile, 95% acetonitrile to 2.4 min, 4% acetonitrile 2.45
min; flow rate 1 ml/min; column 0.4 .mu.L (YMC J'sphere ODS H80
20X2 1.4.mu.); 30.degree. C.)
Example 4
N-Hydroxy-3-methyl-2-(2-oxo-3-(4-phenoxybenzyl)imidazolidin-1-yl)-butyrami-
de
N-Hydroxy-3-methyl-2-(2-oxo-3-(4-phenoxybenzyl)imidazolidin-1-yl)butyrami-
de (14 mg) was obtained from valine t-butyl ester hydrochloride in
analogy to the procedure in 3.3. MS: 384.15 (M+H); R.sub.t: 1.45
min (method: gradient 0 min 96% H.sub.2O (0.05% TFA) 2.0 min 95%
acetonitrile, 95% acetonitrile to 2.4 min, 4% acetonitrile 2.45
min; flow rate 1 ml/min; column 0.4 .mu.L (YMC J'sphere ODS H80
20X2 14.mu.); 30.degree. C.)
Example 5
2-(3-(6-Benzyloxypyridin-3-ylmethyl)-2-oxoimidazolidin-1-yl)-N-hydroxy-3-m-
ethylbutyramide
2-(3-(6-Benzyloxypyridin-3-ylmethyl)-2-oxoimidazolidin-1-yl)-N-hydroxy-3--
methylbutyramide (31 mg) was obtained from valine t-butyl ester
hydrochloride in analogy to the procedure in 3.3. MS: 399.25 (M+H);
R.sub.t: 1.43 min (method: gradient acetonitrile+0.08% formic acid:
H.sub.2O+0.1% formic acid from 5:95 (0 min) to 95:5 (2.5 min) to
95:5 (3 min); flow rate 1.3 ml/min; column YMC Jsphere 33*2.1)
Example 6
2-(3-Biphenyl-4-ylmethyl-2-oxoimidazolidin-1-yl)-N-hydroxy-3-methylbutyram-
ide
2-(3-Biphenyl-4-ylmethyl-2-oxoimidazolidin-1-yl)-N-hydroxy-3-methylbutyra-
mide (101 mg) was obtained from valine t-butyl ester hydrochloride
in analogy to the procedure in 3.3. MS: 398.29 (M+H); R.sub.t: 1.92
min (method: gradient acetonitrile+0.08% formic acid: H.sub.2O+0.1%
formic acid from 5:95 (0 min) to 95:5 (2.5 min) to 95:5 (3 min);
flow rate 1.3 ml/min; column YMC Jsphere 33*2.1)
Example 7
2-(3-Benzyl-5-(4-methoxyphenyl)-2-oxoimidazolidin-1-yl)-N-hydroxy-3-methyl-
butyramide
2-(3-Benzyl-5-(4-methoxyphenyl)-2-oxoimidazolidin-1-yl)-N-hydroxy-3-methy-
lbutyramide (16 mg) was obtained from 1-(4-methoxyphenyl)ethanone
in analogy to the procedure in 3.4. MS: 398.15 (M+H); R.sub.t: 1.31
min (method: gradient 0 min 96% H.sub.2O (0.05% TFA) 2.0 min 95%
acetonitrile, 95% acetonitrile to 2.4 min 4% acetonitrile 2.45 min;
flow rate 1 ml/min; column 0.4 .mu.L (YMC J'sphere ODS H80 20X2
1.4.mu.); 30.degree. C.)
Example 8
N-Hydroxy-2-(3-(4-hydroxybenzyl)-2-oxoimidazolidin-1-yl)-3-methylbutyramid-
e
N-Hydroxy-2-(3-(4-hydroxybenzyl)-2-oxoimidazolidin-1-yl)-3-methylbutyrami-
de (5 mg) was obtained from ethyl
2-(3-(4-benzyloxybenzyl)-2-oxoimidazolidin-1-yl)-3-methylbutyrate
in analogy to the procedure in 3.5. MS: 308.21 (M+H); R.sub.t: 1.29
min (method: gradient acetonitrile+0.08% formic acid: H.sub.2O+0.1%
formic acid from 5:95 (0 min) to 95:5 (2.5 min) to 95:5 (3 min);
flow rate 1.3 ml/min; column YMC Jsphere 33*2.1)
Example 9
N-Hydroxy-2-(3-(3-hydroxybenzyl)-2-oxoimidazolidin-1-yl)-3-methylbutyramid-
e
N-Hydroxy-2-(3-(3-hydroxybenzyl)-2-oxoimidazolidin-1-yl)-3-methylbutyrami-
de (8 mg) was obtained from t-butyl
2-(3-(3-benzyloxybenzyl)-2-oxoimidazolidin-1-yl)-3-methylbutyrate
in analogy to the procedure in 3.5. MS: 308.15 (M+H); R.sub.t: 0.97
min (method: gradient 0 min 96% H.sub.2O (0.05% TFA) 2.0 min 95%
acetonitrile, 95% acetonitrile to 2.4 min, 4% acetonitrile 2.45
min; flow rate 1 ml/min; column 0.4 .mu.L (YMC J'sphere ODS H80
20X2 1.4.mu.); 30.degree. C.)
Example 10
N-Hydroxy-3-methyl-2-{2-oxo-3-(4-(pyridin-4-ylmethoxy)benzyl)imidazolidin--
1-yl}-butyramide; compound with TFA
N-Hydroxy-3-methyl-2-{2-oxo-3-(4-(pyridin-4-ylmethoxy)benzyl)imidazolidin-
-1-yl}-butyramide; compound with TFA (9 mg) was obtained from ethyl
2-(3-(4-benzyloxybenzyl)-2-oxoimidazolidin-1-yl)-3-methylbutyrate
in analogy to the procedure in 3.5. MS: 399.40 (M+H); R.sub.t: 0.78
min (method: gradient 0 min 96% H.sub.2O (0.05% TFA) 2.0 min 95%
acetonitrile, 95% acetonitrile to 2.4 min, 4% acetonitrile 2.45
min; flow rate 1 ml/min; column 0.4 .mu.L (YMC J'sphere ODS H80
20X2 1.4.mu.); 30.degree. C.)
Example 11
N-Hydroxy-3-methyl-2-[2-oxo-3-(4-(pyridin-3-ylmethoxy)benzyl)imidazolidin--
1-yl]-butyramide with TFA
N-Hydroxy-3-methyl-2-{2-oxo-3-(4-(pyridin-3-ylmethoxy)benzyl)imidazolidin-
-1-yl}-butyramide with TFA (6 mg) was obtained from ethyl
2-(3-(4-benzyloxybenzyl)-2-oxoimidazolidin-1-yl)-3-methylbutyrate
in analogy to the procedure in 3.5. MS: 399.45 (M+H); R.sub.t: 0.77
min (method: gradient 0 min 96% H.sub.2O (0.05% TFA) 2.0 min 95%
acetonitrile, 95% acetonitrile to 2.4 min, 4% acetonitrile 2.45
min; flow rate 1 ml/min; column 0.4 .mu.L (YMC J'sphere ODS H80
20X2 1.4.mu.); 30.degree. C.)
Example 12
N-Hydroxy-3-methyl-2-{2-oxo-3-(4-(pyridin-2-ylmethoxy)benzyl)imidazolidin--
1-yl}butyramide with TFA
N-Hydroxy-3-methyl-2-{2-oxo-3-(4-(pyridin-2-ylmethoxy)benzyl)imidazolidin-
-1-yl}-butyramide with TFA (6 mg) was obtained from ethyl
2-(3-(4-benzyloxybenzyl)-2-oxoimidazolidin-1-yl)-3-methylbutyrate
in analogy to the procedure in 3.5. MS: 399.45 (M+H); R.sub.t: 0.79
min (method: gradient 0 min 96% H.sub.2O (0.05% TFA) 2.0 min 95%
acetonitrile, 95% acetonitrile to 2.4 min, 4% acetonitrile 2.45
min; flow rate 1 ml/min; column 0.4 .mu.L (YMC J'sphere ODS H80
20X2 1.4.mu.); 30.degree. C.)
Example 13
2-(3-(4-But-2-ynyloxybenzyl)-2-oxoimidazolidin-1-yl)-N-hydroxy-3-methylbut-
yramide
2-(3-(4-But-2-ynyloxybenzyl)-2-oxoimidazolidin-1-yl)-N-hydroxy-3-methylbu-
tyramide (4 mg) was obtained from ethyl
2-(3-(4-benzyloxybenzyl)-2-oxoimidazolidin-1-yl)-3-methylbutyrate
in analogy to the procedure in 3.5. MS: 360.45 (M+H); R.sub.t: 1.15
min (method: gradient 0 min 96% H.sub.2O (0.05% TFA) 2.0 min 95%
acetonitrile, 95% acetonitrile to 2.4 min, 4% acetonitrile 2.45
min; flow rate 1 ml/min; column 0.4 .mu.L (YMC J'sphere ODS H80
20X2 1.4.mu.); 30.degree. C.)
Example 14
N-Hydroxy-3-methyl-2-{3-(4-(2-methylquinolin-4-ylmethoxy)benzyl)-2-oxoimid-
azolidin-1-yl}butyramide with TFA
N-Hydroxy-3-methyl-2-{3-(4-(2-methylquinolin-4-ylmethoxy)benzyl)-2-oxoimi-
dazolidin-1-yl}-butyramide with TFA (4 mg) was obtained from ethyl
2-(3-(4-benzyloxybenzyl)-2-oxoimidazolidin-1-yl)-3-methylbutyrate
in analogy to the procedure in 3.5. MS: 463.55 (M+H); R.sub.t: 0.89
min (method: gradient 0 min 96% H.sub.2O (0.05% TFA) 2.0 min 95%
acetonitrile, 95% acetonitrile to 2.4 min, 4% acetonitrile 2.45
min; flow rate 1 ml/min; column 0.4 .mu.L (YMC J'sphere ODS H80
20X2 1.4.mu.); 30.degree. C.)
Example 15
2-(3-Benzyl-5-(4-methoxybenzyl)-2-oxoimidazolidin-1-yl)-N-hydroxy-3-methyl-
butyramide
2-(3-Benzyl-5-(4-methoxybenzyl)-2-oxoimidazolidin-1-yl)-N-hydroxy-3-methy-
lbutyramide (92 mg) was obtained from 4-allylanisole in analogy to
the procedure in 3.6. MS: 412.20 (M+H); R.sub.t: 1.35 min (method:
gradient 0 min 96% H.sub.2O (0.05% TFA) 2.0 min 95% acetonitrile,
95% acetonitrile to 2.4 min, 4% acetonitrile 2.45 min; flow rate 1
ml/min; column 0.4 .mu.L (YMC J'sphere ODS H80 20X2 1.4.mu.);
30.degree. C.)
Example 16
2-(3-(4-Benzyloxybenzyl)-5-(4-methoxybenzyl)-2-oxoimidazolidin-1-yl)-N-hyd-
roxy-3-methylbutyramide
2-(3-(4-Benzyloxybenzyl)-5-(4-methoxybenzyl)-2-oxoimidazolidin-1-yl)-N-hy-
droxy-3-methylbutyramide (55 mg) was obtained from 4-allylanisole
in analogy to the procedure in 3.6. MS: 518.29 (M+H); R.sub.t: 2.54
min (method: gradient acetonitrile+0.05% TFA:H.sub.2O+0.05% TFA
from 5:95 (0 min) to 95:5 (3.4 min) to 95:5 (4.4 min); flow rate 1
ml/min; column YMC Jsphere 33*2)
Example 17
N-Hydroxy-2-(5-(4-methoxybenzyl)-3-methyl-2-oxoimidazolidin-1-yl)-3-methyl-
butyramide
N-Hydroxy-2-(5-(4-methoxybenzyl)-3-methyl-2-oxoimidazolidin-1-yl)-3-methy-
lbutyramide (80 mg) was obtained from 4-allylanisole in analogy to
the procedure in 3.6. MS: 336.22 (M+H); R.sub.t: 1.62 min (method:
gradient acetonitrile+0.05% TFA:H.sub.2O+0.05% TFA from 5:95 (0
min) to 95:5 (3.4 min) to 95:5 (4.4 min); flow rate 1 ml/min;
column YMC Jsphere 33*2)
Example 18
2-(5-Benzo(1,3)dioxol-5-ylmethyl-3-(4-benzyloxybenzyl)-2-oxoimidazolidin-1-
-yl)-N-hydroxy-3-methylbutyramide
2-(5-Benzo(1,3)dioxol-5-ylmethyl-3-(4-benzyloxybenzyl)-2-oxoimidazolidin--
1-yl)-N-hydroxy-3-methylbutyramide (110 mg) was obtained from
4-allylanisole in analogy to the procedure in 3.6. MS: 532.31
(M+H); R.sub.t: 2.62 min (method: gradient acetonitrile+0.05%
TFA:H.sub.2O+0.05% TFA from 5:95 (0 min) to 95:5 (3.4 min) to 95:5
(4.4 min); flow rate 1 ml/min; column YMC Jsphere 33*2)
Example 19
2-(5-Benzo(1,3)dioxol-5-ylmethyl-3-benzyl-2-oxoimidazolidin-1-yl)-N-hydrox-
y-3-methylbutyramide
2-(5-Benzo(1,3)dioxol-5-ylmethyl-3-benzyl-2-oxoimidazolidin-1-yl)-N-hydro-
xy-3-methylbutyramide (100 mg) was obtained from 4-allylanisole in
analogy to the procedure in 3.6. MS: 426.26 (M+H); R.sub.t: 2.07
min (method: gradient acetonitrile+0.05% TFA:H.sub.2O+0.05% TFA
from 5:95 (0 min) to 95:5 (3.4 min) to 95:5 (4.4 min); flow rate 1
ml/min; column YMC Jsphere 33*2)
Example 20
2-(5-(4-Benzyloxybenzyl)-3-(4-methoxybenzyl)-1,1-dioxo-(1,2,5)thiadiazolid-
in-2-yl)-N-hydroxy-3-methylbutyramide
2-(5-(4-Benzyloxybenzyl)-3-(4-methoxybenzyl)-1,1-dioxo-(1,2,5)thiadiazoli-
din-2-yl)-N-hydroxy-3-methylbutyramide (17 mg) was obtained from
4-allylanisole in analogy to the procedure in 3.6. MS: 554.37
(M+H); R.sub.t: 2.57 min (method: gradient acetonitrile+0.05%
TFA:H.sub.2O+0.05% TFA from 5:95 (0 min) to 95:5 (3.4 min) to 95:5
(4.4 min); flow rate 1 ml/min; column YMC Jsphere 33*2)
PHARMACOLOGICAL EXAMPLES
The activity of the cyclic urea derivatives of the invention was
tested in various in vitro assay systems for inhibitory activity on
the proteases ADAMTS-4 and TNF.alpha.-converting enzyme (TACE) and
on matrix-degrading metalloproteases (MMP13).
The ADAMTS-4 activity was measured using a recombinantly prepared
human ADAMTS-4 protease and the rAgg1mut substrate. The rAgg1mut
substrate comprises the interglobular domain of the human aggrecan
molecule fused N-terminally to a FLAG sequence and fused
C-terminally to a human IgG Fc portion. In the interglobular domain
there is a specific cleavage site for ADAMTS-4, cleavage of which
generates a new N-terminal epitope which can be measured by means
of a neo-epitope-specific monoclonal antibody in an ELISA test
system (Horber, C., Buttner, F H., Kern, C., Schmiedeknecht, G.
& Bartnik, E. (2000), Matrix Biology 19, 533-543).
The activity in relation to TACE was measured using a commercially
available, recombinantly prepared TACE protease (R&D Systems)
and the substrate MCA-ProLeuAlaGlnAlaVal-Dpa-ArgSerSerSerArg-NH2
(Bachem). Cleavage of the TACE-specific substrate is measured in a
fluorimeter with the wavelengths Ex 320 nm/Em 405 nm, and the
amount of cleaved substrate is determined from a calibration
plot.
The activities in relation to MMP13 were measured using
recombinantly prepared enzymes from various manufacturers
(Biotrend, Roche, Boehringer Mannheim) and with various
MMP-specific peptide substrates (Bachem). Cleavage of the
MMP-specific substrates was measured after APMA activation of the
proteases at pH 7.5 or pH 6.5 in a fluorimeter at the wavelengths
of Ex 340 nm/Em 405 nm.
The proteoglycan degradation was determined using primary bovine
chondrocytes which were isolated from the cartilage of the
metacarpophalangeal joint of cattle about 6 months old and cultured
in an alginate matrix at 37.degree. C. and 5% CO.sub.2 for 3 weeks.
Stimulation of .about.160 000 cells with 5 ng/ml human IL1.alpha.
was followed after 16 hours by determination of the liberated
amount of proteoglycan by means of a commercially available
dimethylmethylene blue dye test system (Biocolor Ltd.).
Inhibition of ADAMTS-4 Activity (IC50 in .mu.M):
TABLE-US-00001 Example 1 2 4 5 6 9 10 11 12 14 15 16 18 ADAMTS-4
2.1 55 1.33 10 9.06 72.39 0.9 7.8 7.0 1.14 17 1.39 3.16
Inhibition of MMP 13 Activity (IC50 in .mu.M):
TABLE-US-00002 Example 1 4 7 10 11 15 16 17 18 19 20 MMP13 5.0 0.08
0.01 4.0 5.4 0.4 0.42 3.17 0.6 0.34 3.58
Inhibition of TACE activity (IC50 in .mu.M):
TABLE-US-00003 Example 1 3 4 7 9 10 11 12 13 14 15 16 18 19 TACE
2.47 2.0 5.0 9.0 3.04 1.14 3 8 5 0.01 8 3.08 1.9 9.29
Inhibition of Proteoglycan Liberation from IL1.alpha.-Stimulated
Primary Bovine Chondrocyte Cultures:
TABLE-US-00004 Example 1 10 14 16 Inhibition of proteoglycan >50
>50 12.9 25.5 liberation (IC50 in .mu.M) (> = more than)
* * * * *